Handbook of Evidence Based SRS and SBRT 2016

Rajni A. Sethi · Igor J.
Barani
David A. Larson · Mack Roach, III
Editors
Handbook of
Evidence-Based
Stereotactic
Radiosurgery and
Stereotactic Body
Radiotherapy
123
Handbook of Evidence-Based
Stereotactic Radiosurgery
and Stereotactic Body
Radiotherapy
Rajni A. Sethi • Igor J. Barani
David A. Larson • Mack Roach, III
Editors
Handbook of
Evidence-Based
Stereotactic
Radiosurgery
and Stereotactic Body
Radiotherapy
Editors
Rajni A. Sethi, MD Igor J. Barani, MD

Department of Radiation Departments of Radiation
Oncology Oncology and Neurological
University of California, Surgery
San Francisco University of California,
San Francisco, CA, USA San Francisco
San Francisco, CA, USA
David A. Larson, MD, PhD
Departments of Radiation Mack Roach, III, MD
Oncology and Neurological Department of Radiation
Surgery Oncology and Urology
University of California, University of California,
San Francisco San Francisco
San Francisco, CA, USA San Francisco, CA, USA
ISBN 978-3-319-21896-0 ISBN 978-3-319-21897-7 (eBook)

DOI 10.1007/978-3-319-21897-7
Library of Congress Control Number: 2015945109
Springer Cham Heidelberg New York Dordrecht London

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Preface
Over the past decade, technical advancements in radiother-

apy such as image guidance, highly modulated beams,
improved patient immobilization, tumor tracking systems,
beam gating, and complex treatment planning systems have
enabled practitioners to accurately and precisely deliver
highly conformal, large doses of radiation. As these tech-
nologies are more widely adopted worldwide, extreme hypo-
fractionated and single fraction regimens using stereotactic
radiosurgery (SRS) and stereotactic body radiotherapy
(SBRT) are becoming more common. We developed this
handbook in order to concisely summarize the state of the
art including: (1) history of SRS and SBRT; (2) the biologic
rationale; (3) typical practices; and (4) the reported results.
In doing so, we hope that practitioners might be more aware
of what has been published and what might be expected
were they to similarly treat patients. However, we cannot
and do not vouch for the safety of any of treatment practices
reported. First, the follow-up in many cases is relatively
short. Second, as with any recipe, there may be details or
ingredients left out that may critically impact the results. In
all cases clinical judgment is required, particularly in cases
when dose-limiting structures are put at risk when adjacent
to very high doses of radiation.
While several textbooks focus on SRS and SBRT, we spe-
cifically wanted to create a practical handbook on these tech-
niques that could be referenced easily in the clinic. This
handbook can inform decisions regarding the appropriateness
v
vi Preface
of SRS or SBRT, guide treatment technique, and summarize

expected outcomes and toxicity.
We have developed the Handbook of Evidence-Based
Stereotactic Radiosurgery and Stereotactic Body Radiotherapy
as a companion book to our institution’s prior publication,
Handbook of Evidence-Based Radiation Oncology. As such,
we have attempted not to replicate information between the
two books. General information on anatomy, staging, work-
up, and follow-up for each disease site can be referenced in
the latter. The current handbook focuses on specific uses of
SRS and SBRT, with chapters organized by disease site. We
include a description of treatment techniques and recom-
mended imaging. We also specifically address safety and
quality assurance issues, which are especially important with
extreme hypofractionation. In each chapter, we discuss toxic-
ity and management issues specific to SBRT. We have also
included chapters on the historical development of SRS and
SBRT, biologic rationale for these techniques, and treatment
delivery systems. Finally, in the appendix, we include a sum-
mary of normal tissue dose tolerances.
In order to maintain the nature of this publication as a
handbook, we limited the amount of information included in
each chapter. We encourage you to refer to original publica-
tions as listed in the reference section for more detailed infor-
mation on clinical protocols and previously published data.
In many cases the contents of this book reflect the treat-
ment approach at the University of California at San
Francisco. We are privileged to employ a broad range of
treatment machines and expertise that enables the use of
SRS and SBRT in many settings. This book is meant to sum-
marize our own experience and that of our colleagues who
have reported separately in peer-reviewed journals and at
national and international meetings. Individual practitioners
must use their own clinical judgment and knowledge to guide
use of SRS and SBRT in their own practice. Specifically, we
caution against use of these highly skilled techniques in insti-
tutions without prior training or expertise.
Preface vii
We want to sincerely thank the contributing authors for

the excellent chapters they have produced. We also wanted to
specifically thank Keith Sharee for his stalwart and enthusi-
astic editorial review and for managing all of the references
and abbreviations. This handbook would not have been pos-
sible without their hours of hard work and dedication. We
want to acknowledge the pioneers in our field who have built
the body of work that we are presenting here today and
whose ingenuity and drive continues to move our field ahead
with the constant goal of improving outcomes for our
patients. And finally, we want to thank our patients, whose
courage continues to inspire us every day.
San Francisco, CA, USA Rajni A. Sethi, MD

Igor J. Barani, MD
Mack Roach, III, MD
Abbreviations
AAPM American Association of Physicists in Medicine

ABC Active breathing control
ACTH Adrenocorticotropic hormone
ADT Androgen deprivation therapy
AFP Alpha-fetoprotein (α-fetoprotein)
AMA American Medical Association
AP/PA Anteroposterior/posteroanterior
ASTRO American Society for Radiation Oncology
ATM Ataxia telangiectasia mutated
ATR ATM-Rad3-related
AVM Arterio-venous malformation
BED Biologically effective dose
bPFS Biochemical progression-free survival
BPL Batho power-law correction
BRCA Breast cancer risk genes BRCA1 and BRCA2
BUN Blood urea nitrogen
CAD Coronary artery disease
CBC Complete blood count
CBCT Cone beam computed tomography
CEA Carcinoembryonic antigen
CGE Cobalt gray equivalent
CHF Congestive heart failure
CK CyberKnife
Cm Centimeter
CMP Comprehensive metabolic panel
CMS Centers for Medicare and Medicaid Services
CN Cranial nerve
CNS Central nervous system
ix
x Abbreviations
COPD Chronic obstructive pulmonary disease

CPA Cerebellopontine angle
CPT Current procedural terminology
Cr Creatinine
CR Complete response
CRT Conformal radiation therapy
CSF Cerebrospinal fluid
CSS Cause-specific survival
CT Computerized tomography
CT A/P CT abdomen pelvis
CT C/A/P CT chest abdomen pelvis
ctDNA Circulating tumor DNA
CTV Clinical target volume
CXR Chest X-ray
DBR Distant brain recurrence
DLCO Carbon monoxide diffusion in the lung
DNA Deoxyribonucleic acids
DRE Digital rectal examination
DRR Digitally reconstructed radiograph
DSS Disease-specific survival
EBRT External beam radiation therapy
ECOG Eastern Cooperative Oncology Group
EGFR Epidermal growth factor receptor
EORTC European Organisation for Research
and Treatment of Cancer
EPID Electronic portal imaging devices
EQD2 Equivalent dose in 2 Gy fractions
ERCP Endoscopic retrograde
cholangiopancreatography
ESR Erythrocyte sedimentation rate
EUA Exam under anesthesia
EUS Endoscopic ultrasound
FCRT Fractionated conformal radiotherapy
FDG Fluoro-deoxy-glucose (fludeoxyglucose)
FEV1 Forced Expiratory Volume (In 1 s)
FFLP Freedom from local progression
FFP Freedom from progression
FLAIR Fluid attenuation inversion recovery
Abbreviations xi
FNA Fine needle aspiration

FSH Follicle-stimulating hormone
5FU 5-Fluorouracil
FVC Forced vital capacity
GGO Ground glass opacities
GH Growth hormone
GI Gastrointestinal
GIST Gastrointestinal stromal tumor
GKRS Gamma knife radiosurgery
GS Gleason score
GSM Gold seed marker
GTR Gross total resection
GTV Gross tumor volume
GU Genitourinary
Gy Gray
H&P History and physical
HCC Hepatocellular carcinoma
HDR High dose rate
HNSCC Head and neck squamous cell carcinoma
HPV Human papillomavirus
HR Homologous recombination or Hazard ratio
ICRU International Commission on Radiation Units
and Measurements
IDL Isodose line
IGRT Image-guided radiation therapy
iGTV Internal gross tumor volume
ILD Interstitial lung disease
IMRT Intensity modulated radiation therapy
INR International normalized ratio
IORT Intraoperative radiation therapy
ITV Internal target volume
IV Intravenous
IVC Inferior vena cava
IVP Intravenous pyelogram
JROSG Japanese Radiation Oncology Study Group
KPS Karnofsky performance scale
kV Kilovolt
xii Abbreviations
LC Local control
LDH Lactate dehydrogenase
LF Local failure
LFT Liver function test
LH Luteinizing hormone
LPFS Local progression-free survival
LQ Linear quadratic
MDACC MD Anderson Cancer Center
MeV Mega electron volt
MFS Metastasis-free survival
MLC Multileaf collimator
Mm Millimeter
MMEJ Microhomology-mediated end joining
MMSE Mini-mental state examination
MNLD Maximal nonlethal dose
MRA Magnetic resonance angiogram
MRCP Magnetic resonance cholangiopancreatography
MRI Magnetic resonance imaging
MRN MRE11-Rad50-NBS1
MS Median survival
MTD Maximum tolerated dose
MTP Mean target position
MU Monitor units
MV Megavolt
MVCT Megavoltage CT
MVD Microvascular decompression
NAA N-acetyl-aspartic acid
NAGKC North American Gamma Knife Consortium
NCCN National Comprehensive Cancer Network
NED No evidence of disease
NF2 Neurofibromatosis type II
NHEJ Non-homologous end joining
NR Not reported
NSAID Nonsteroidal anti-inflammatory drug
NSCLC Non-small cell lung cancer
OAR Organs at risk
ODI Optical distance indicator
OS Overall survival
Abbreviations xiii
PALN Para-aortic lymph nodes

PCP Pneumocystis carinii pneumonia
PDD Percent depth dose
PET Positron emission tomography
PFP Progression-free probabilities
PFS Progression-free survival
PR Partial response
PSA Prostate-specific antigen
PTV Planning target volume
QA Quality assurance
QOD Every other day
QOL Quality of life
RBE Relative biological effectiveness
RCC Renal cell carcinoma
RECIST Response evaluation criteria in solid tumors
RFA Radiofrequency ablation
RILD Radiation-induced liver damage
RP Radical prostatectomy
RPA Recursive partitioning analysis
RPL Radiological path length algorithm
RS Radiosurgery
RT Radiotherapy or radiation therapy
RTOG Radiation Therapy Oncology Group
RUC AMA Specialty Society Relative Value Scale
Update Committee
RVS AMA Specialty Society Relative Value Scale
SABR Stereotactic ablative radiotherapy or stereotactic
ablative brain radiation or stereotactic ablative
body radiotherapy
SAHP Senescence-associated heterochromatin foci
SBRT Stereotactic body radiotherapy
SD Stable disease
SF Surviving fraction
SMA Superior mesenteric artery
SRS Stereotactic radiosurgery
STR Subtotal resection
STS Soft tissue sarcoma
SUV Standardized uptake value
xiv Abbreviations
TIA Transient ischemic attack

TPS Treatment planning system
TRUS Transrectal ultrasound
TSH Thyroid-stimulating hormone
TURBT Transurethral resection of bladder tumor
TURP Transurethral resection of prostate
TVT Tumor vascular thrombosis
U/S Ultrasound
UA Urinalysis
USC Universal survival curve
USPSTF US Preventive Service Task Force
VCF Vertebral body compression fracture
VEGF Vascular endothelial growth factor
VMAT Volumetric-modulated arc therapy
WBRT Whole-brain radiation therapy
WHO World Health Organization
XR X-ray
Contents
1 Introduction to Stereotactic Radiosurgery

and Stereotactic Body Radiotherapy ........................ 1
David A. Larson
Part I Radiobiology of Stereotactic Radiosurgery

and Stereotactic Body Radiotherapy
2 Radiobiology of Stereotactic Radiosurgery

Andrew Vaughan and Shyam S.D. Rao
Part II Physics of Stereotactic Radiosurgery

and Stereotactic Body Radiotherapy
3 Physics of Stereotactic Radiosurgery

Angélica Pérez-Andújar, Martina Descovich,
and Cynthia F. Chuang
Part III Clinical Applications
4 Intracranial Tumors ..................................................... 41

David R. Raleigh, Igor J. Barani, Penny Sneed,
and David A. Larson
5 Spine .............................................................................. 79
David R. Raleigh, Igor J. Barani,
and David A. Larson
xv
xvi Contents
6 Head and Neck ............................................................ 97

Sue S. Yom
7 Lung .............................................................................. 109
Steve E. Braunstein, Sue S. Yom,
and Alexander R. Gottschalk
8 Digestive System.......................................................... 145
David R. Raleigh and Albert J. Chang
9 Genitourinary Sites ..................................................... 165
Michael Wahl, Albert J. Chang,
Alexander R. Gottschalk, and Mack Roach, III
10 Gynecologic Sites ........................................................ 183
Zachary A. Seymour, Rajni A. Sethi,
and I-Chow Joe Hsu
11 Soft Tissue Sarcoma .................................................... 191
Steve E. Braunstein and Alexander R. Gottschalk
12 Extracranial Oligometastases .................................... 203
Jennifer S. Chang, Rajni A. Sethi, and Igor J. Barani
Appendix A: Dose-Volume Criteria ................................. 221
Index...................................................................................... 231
Contributors
Igor J. Barani, MD
Departments of Radiation Oncology and Neurological
Surgery, University of California, San Francisco, San Francisco,
CA, USA
Steve E. Braunstein, MD, PhD
Department of Radiation Oncology, University of California,
San Francisco, San Francisco, CA, USA
Albert J. Chang, MD, PhD
Department of Radiation Oncology, University of
California, San Francisco, San Francisco, CA, USA
Jennifer Chang, MD, PhD
Cynthia F. Chuang, PhD
Martina Descovich, PhD
San Francisco, Helen Diller Family Comprehensive Cancer
Center, San Francisco, CA, USA
Alexander R. Gottschalk, MD, PhD
xvii
xviii Contributors
I-Chow Joe Hsu, MD

Surgery, University of California, San Francisco, San
Francisco, CA, USA
Departments of Radiation Oncology and Neurological Surgery,
University of California, San Francisco, San Francisco, CA, USA
Angélica Pérez-Andújar, PhD
David R. Raleigh, MD, PhD
Shyam S.D. Rao, MD, PhD
Department of Radiation Oncology, University of California
Comprehensive Cancer Center, Sacramento, CA, USA
Mack Roach, III, MD
Department of Radiation Oncology and Urology, University of
Rajni A. Sethi, MD
Zachary A. Seymour, MD
Penny Sneed, MD
Andrew Vaughan, PhD
Comprehensive Cancer Center, Sacramento, CA, USA
Contributors xix
Michael Wahl, MD
Sue S. Yom, MD, PhD
Chapter 1
Introduction to Stereotactic
Radiosurgery and Stereotactic
Body Radiotherapy
David A. Larson
Stereotactic radiosurgery (SRS) and stereotactic body radio-

therapy (SBRT) have an established but evolving role in the
management of malignant and benign conditions. They have
altered the way clinicians think about fractionation, and
therefore they rank among the most important advances in
radiation oncology, along with the development of megavolt-
age treatment machines, imaging-based treatment planning,
and intensity-modulated radiation therapy. SRS and SBRT
technologies were developed largely by dedicated medical
physicists, (Benedict et al. 2008) with input from clinicians.
Approximately 5–10 % of US radiotherapy courses are deliv-
ered with SRS or SBRT, and these technologies and their
clinical outcomes are now a firmly established part of the
educational curriculum for resident physicians in radiation
oncology and neurosurgery.
D.A. Larson ()

University of California, San Francisco, 1600 Divisadero Street,
Basement Level, San Francisco, CA 94143-1708, USA
e-mail: DLarson@radonc.ucsf.edu
© Springer International Publishing Switzerland 2016 1

R.A. Sethi et al. (eds.), Handbook of Evidence-Based
Stereotactic Radiosurgery and Stereotactic Body
Radiotherapy, DOI 10.1007/978-3-319-21897-7_1
2 D.A. Larson
Historical Foundations
During the 1950s, neuroanatomists and neurophysiologists
developed techniques to produce small, highly localized,
ablative CNS radio-lesions in animals using a variety of
radiation sources, including implanted radon seeds, implanted
isotopes such as Au198 and Co60, betatron X-rays, and cyclotron-
produced protons and deuterons. Swedish neurosurgeon Lars
Leksell, a pioneer in the development of stereotaxy, recog-
nized that small, accurately placed radio-lesions could be
produced in humans. In 1951 he coined the term “radiosur-
gery” and is recognized as the father of radiosurgery (Leksell
1951). He performed focal single-fraction experiments in the
brains of goats, cats, and rabbits using multiple cross-fired
proton beams as he sought an optimum dose to produce dis-
crete CNS lesions of dimension 3–7 mm. He found that a
suitable maximum dose for the production of a discrete
lesion within 1–2 weeks was 20 Gy in a single fraction. In the
1950s and 1960s he pioneered X-ray and proton SRS for pain
syndromes and movement disorders. In 1961 he used 3 mm
cross-fired proton beams to perform thalamotomies for pain
control. He invented the Gamma Knife and performed his
first Gamma Knife procedure in 1967. In 1974 that first
Gamma Knife was installed as an experimental tool at
UCLA under the direction of neurosurgeon Bob Rand.
During the 1950s, in the USA, internist John Lawrence, often
called the father of nuclear medicine, developed highly focal
ablative radiation procedures with cyclotron-produced protons,
deuterons, and helium ions at what is now called Lawrence
Berkeley National Laboratory (where John’s brother, Ernest,
invented the cyclotron, for which he was awarded the Nobel
Prize). He took great interest in pituitary disorders and per-
formed multi-fraction dose/targeting studies in dogs, rats, and
monkeys using bone landmarks to target and ablate the pitu-
itary with multiple cross-fired beams. He initiated human stud-
ies in 1954, initially to suppress pituitary function in breast
cancer patients and subsequently to treat acromegaly. He tried
numerous fractionation schemes, eventually settling on 300 Gy
1. Introduction 3
in six fractions over 2 weeks to ablate the pituitary without

damage to the surrounding tissue.
In 1961, Massachusetts General Hospital neurosurgeons
William Sweet and Raymond Kjellberg initiated treatment of
pituitary tumors and arteriovenous malformations with
single-fraction Bragg-peak protons. Kjellberg searched the
literature for examples of brain radio-necrosis in humans,
monkeys, and rats, and plotted his findings as log of dose suf-
ficient to produce necrosis versus log of beam diameter, and
connected the data points with a steep straight line demon-
strating the strong relationship between treatment volume
and likelihood of necrosis. His plot indicated that 10 Gy was
sufficient to produce necrosis for a 10 cm beam diameter and
4000 Gy was sufficient to produce necrosis for a 10 μm beam
diameter (Kjelberg 1979). Many of his initial SRS treatments
involved doses considered just sufficient to cause radionecro-
sis, according to his necrosis plot.
Neurosurgeons in Europe, South America, and the United
States subsequently developed SRS programs using modified
linear accelerators or cobalt teletherapy units. One of the
best known systems was the linac SRS system developed by
neurosurgeon Ken Winston and physicist Wendel Lutz, stim-
ulated by the work of Leksell and designed to be capable of
delivering very high, single-fraction photon radiation doses in
the range of 100–150 Gy to small, precisely located, volumes
(0.5–2 cm3) within the brain (Lutz et al. 1984).
Development of SRS and SBRT

Although the above historical foundations involved focally
ablative lesioning, SRS as it developed in the late 1980s
involved less aggressive single-fraction maximum doses, in the
range of 20–50 Gy for most indications and for treatment vol-
umes up to about 15 cc, with higher maximum doses in the
range of 100–150 Gy reserved for pain syndromes or movement
disorders and for treatment volumes less than about 0.1 cc.
Selection of the less aggressive doses was strongly influenced by
4 D.A. Larson
radiation oncologists and neurosurgeons at the first North

American SRS locations, including Boston (1/86, AVM),
Montreal (12/86, AVM), Pittsburgh (8/87, acoustic neuroma),
and San Francisco (3/88, AVM). Initial treatments at those
facilities and others throughout the world were for benign
rather than malignant indications, even though today the
majority of SRS and nearly all SBRT procedures are for malig-
nant processes. One of the first reported malignant indications
receiving SRS was Sturm’s 1987 report on brain metastasis
(Sturm et al. 1987).
During the late 1980s and early 1990s, SRS grew rapidly.
The first North American Radiosurgery conference was held
in 1987 in Boston, organized by neurosurgeon Ken Winston
and radiation oncologist Jay Loeffler, attracting 100 regis-
trants. ASTRO’s first “refresher” course on radiosurgery,
attended by about 400 members, was presented by radiation
oncologist David Larson at ASTRO’s Annual Meeting in
New Orleans in 1988. The yearly number of SRS patients in
North America increased from about 600 in 1990 to about
12,000 in 2000, during which period the number of yearly
publications on SRS increased from about 50 to about 200.
SBRT developed about a decade later than SRS, but was
based on similar principles. Swedish physicist Ingmar Lax and
radiation oncologist Henric Blomgren, both at the Karolinska
Hospital in Stockholm, were very familiar with the brain SRS
procedures being carried out in their institution. They rea-
soned that similar local control outcomes could be achieve at
non-brain body sites with one or a few focally delivered frac-
tions, even if targeting and immobilization issues for non-
brain sites were more much complicated. They described
their technique in 1994 (Lax et al. 1994) and in 1995 reported
clinical outcomes in 31 patients with 42 malignant tumors of
the liver, lung, or retroperitoneum, achieving local control in
80 % of targets, and prescribing at the 50 % isodose surface
(Blomgren et al. 1995). David Larson visited the Karolinska
Hospital in 1993 as an observer and brought their technique
back to UCSF, where he treated 150 patients during 1993–
1995. Thus the origins of both SRS and SBRT can be traced
to the Karolinska Hospital.
1. Introduction 5
Standard Fractionation Versus

Hypofractionation
Prominent pioneers of standard fractionation include French
radiation oncologists Henri Coutard and Francois Baclesse,
who treated laryngeal and breast cancers in Paris with vari-
ous fractionation schemes lasting from 2 weeks to 10 months
during the 1920s–1940s. They found that the uncomplicated
control rate, often called the therapeutic ratio, peaked at 6–8
weeks, a result championed by Gilbert Fletcher in the USA
following his training in Paris and confirmed by years of clini-
cal experience throughout the world. In 1997, radiation
oncologist Eli Glatstein stated: “Had Coutard and Baclesse
not pioneered fractionation, radiotherapy probably would
have fallen into oblivion due to the morbidities of single shot
treatment. Indeed, much of the first half of this century was
spent learning that doses large enough to sterilize a mass of
tumor cells (10 logs) cannot be predictably given safely.
Instead, fractionation evolved which permitted us to exploit
repopulation, redistribution, reoxygenation, and repair.”
Despite the above, clinicians have found that SRS- and
SBRT-based hypofractionation techniques can be effectively
and safely used for benign and malignant conditions in the
brain and for initial or recurrent non-small-cell lung cancer,
prostate cancer, renal cell carcinoma, and hepatocellular can-
cer, and for oligometastases in the lung, liver, spine, and brain.
To reconcile this with the established role of standard frac-
tionation, one must recognize that with non-focal radiother-
apy the number of normal cells irradiated to full dose was
historically as much as several logs greater than the number
of tumor cells irradiated. However, with SRS and SBRT, the
number of normal cells irradiated to full dose is as much as a
log less than the number of tumor cells irradiated. If few nor-
mal tissue cells receive full dose, any clinically observable
benefits of standard fractionation that are attributable to
repopulation and repair are necessarily diminished. Similarly,
the clinically observable fractionation benefits attributable to
reoxygenation and redistribution within tumors are dimin-
ished if BED within the target can be increased safely.
6 D.A. Larson
For small tumors such as acoustic neuromas, meningiomas,

and brain metastases, the reported uncomplicated control
rate curve appears to be relatively flat over the range of 1–30
fractions. For some slightly larger targets, perhaps up to
3–5 cm in maximum dimension, the rates may peak at about
5 fractions, possibly because of the increased importance of
reoxygenation and the increased volume of irradiated normal
tissue with larger targets. Nevertheless, it is recognized that
for many targets at CNS and non-CNS sites, the precise opti-
mum fraction number with highly focal SRS or SBRT is not
known, even though it is almost certainly far less than 30.
Summary
In summary, clinical results indicate that for carefully selected
small targets of most histologies and at most anatomic body
sites, favorable uncomplicated control rates can be achieved
with 1–5 SRS or SBRT fractions, as the following chapters
demonstrate. Nevertheless, physician judgment remains para-
mount, and in that context it is appropriate to quote Professor
Franz Buschke, ex-Chair of Radiation Oncology at UCSF,
who wrote a letter to a referring physician in which he said:
“Coutard taught us that the incidence of radiation sickness is
related to the incompetence of the radiation therapist.”
(Letter to a referring physician 1952).
Nomenclature
The terms “SRS” and “SBRT,” as used in this manual, apply
to CNS and non-CNS anatomic sites, respectively, and in both
cases involve delivery of a high biological effective dose
(BED) in 1–5 fractions to small, focal, well-defined targets
while minimizing nontarget dose. In the USA this terminol-
ogy is recognized by the American Medical Association
(AMA) Current Procedural Terminology (CPT) editorial
panel, the AMA Specialty Society Relative Value Scale
1. Introduction 7
(RVS) Update Committee (RUC), the Centers for Medicare

and Medicaid Services (CMS), and most commercial payers.
Alternative nomenclature such as “SABR” (“Stereotactic
Ablative Radiotherapy” or “Stereotactic Ablative Brain
Radiation” or “Stereotactic Ablative Body Radiotherapy”) is
favored by some marketers.
References
Benedict SH, Bova FJ, Clark B, Goetsch SJ, Hinson WH, Leavitt DD,
et al. Anniversary paper: the role of medical physicists in devel-
oping stereotactic radiosurgery. Med Phys. 2008;35(9):4262–77.
Blomgren H, Lax I, Naslund I, Svanstrom R. Stereotactic high dose
fraction radiation therapy of extracranial tumors using an accel-
erator. Clinical experience of the first thirty-one patients. Acta
Oncol. 1995;34(6):861–70.
Kjelberg R. Isoeffective dose parameters for brain necrosis in rela-
tion to proton radiosurgical dosimetry. Stereotactic cerebral irra-
diation. INSERM symposium no 12: proceedings of the INSERM
Symposium on Stereotactic Irradiations held in Paris (France), 13
July 1979. G. Szikla. Amsterdam; New York, New York, Elsevier/
North-Holland Biomedical Press; sole distributors for the USA
and Canada, North Holland: Elsevier; 1979. pp. 157–66.
Lax I, Blomgren H, Naslund I, Svanstrom R. Stereotactic radiother-
apy of malignancies in the abdomen. Methodological aspects.
Acta Oncol. 1994;33(6):677–83.
Leksell L. The stereotaxic method and radiosurgery of the brain.
Acta Chir Scand. 1951;102(4):316–9.
Lutz W, Winston K, Maleki N, Cassady R, Svensson G, Zervas
N. Stereotactic radiation surgery in the brain using a 6 MV linear
accelerator. Int J Radiat Oncol Biol Phys. 1984;10 Suppl 2:189.
Sturm V, Kober B, Höver KH, Schlegel W, Boesecke R, Pastyr O,
Hartmann GH, Schabbert S, zum Winkel K, Kunze S,
et al. Stereotactic percutaneous single dose irradiation of brain
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1987;13(2):279–82.
Part I
Radiobiology of Stereotactic
Body Radiotherapy
Chapter 2
Radiobiology of Stereotactic
Body Radiotherapy
Andrew Vaughan and Shyam S.D. Rao
Historically, the radiation biology relevant to clinical treatment

was developed in a pre-IGRT era where normal tissues received
substantial, protracted irradiation. This conventional fraction-
ated treatment, commonly involving 30–35 fractions of 1.8–2 Gy
over 6–7 weeks, has been interpreted biologically with the
parameters, repair, reoxygenation, redistribution, repopulation,
and (less commonly) radiosensitivity. Hypofractionated treat-
ment may modify the impact or significance of these factors.
Repair
It is widely assumed that irradiated normal tissue is better
able to respond to repetitive cycles of DNA damage than
tumors, linked to intrinsic aberrations in damage repair
systems characteristic of transformation (Jackson and Bartek
2009). Thus multiple fractions of irradiation incrementally
A. Vaughan (*) • S.S.D. Rao

Comprehensive Cancer Center, 4501 X Street, Sacramento,
CA 95817, USA
e-mail: andrew.vaughan@ucdmc.ucdavis.edu

12 A. Vaughan and S.S.D. Rao
separate normal tissue toxicity from that seen in the tumor.

During SRS/SBRT the number of fractions delivered is much
reduced, limiting the magnitude of this differential response,
however offset by reduced normal tissue damage linked to
precision dose delivery. As the opportunity for repair is
reduced the toxicity of the dose delivered is greater, a fea-
ture linked to the beta (quadratic) term of the linear qua-
dratic equation discussed later. Individual DNA break sites
are tagged with a modified histone, γ H2AX, over large, Mbp
tracts of DNA surrounding the break, which can be visual-
ized using labeled antibodies (Valdiglesias et al. 2013). The
break itself is marked by the MRN complex of MRE11,
Rad50, and Nibrin that holds the two broken ends together.
Individual breaks may be repaired by one of the three sys-
tems, homologous recombination (HR), nonhomologous
end joining (NHEJ) or microhomology-mediated end join-
ing (MMEJ) also called backup NHEJ. In the order written
these repair pathways offer an increasing chance of mis-
repair, thus generating lethal aberrations such as a dicentric
rearrangement.
Reoxygenation
Tumors commonly exhibit localized hypoxia (≤10 mmHg).
The lack of oxygen is a potent dose modifier increasing radia-
tion resistance by up to a factor of three due to the lack of
fixation of free radical damage. Conventional fractionation
facilitates reoxygenation by reducing overall oxygen demand
as the tumor mass shrinks under treatment. Residual hypoxic
cells may become reoxygenated late in the treatment cycle,
and thus be eradicated. SRS/SBRT is at a theoretical disad-
vantage in that it offers both a reduced time frame and number
of fractions to initiate and utilize reoxygenation. Further
research will be required to determine the significance of this
issue. Hypoxic cell sensitizers, such as the nitroimidazoles,
have been modestly effective in initial clinical trials but have
not gained widespread clinical acceptance as more recent
2. Radiobiology 13
data have shown minimal efficacy (Reddy and Williamson

2009; Rischin et al. 2010). Their application to SRS/SBRT may
be more appropriate in that the need for hypoxic sensitization
may be greater and the reduced treatment time may limit
patient exposure to toxic side effects. Hypoxic tumor content
alone is a negative predictor of outcome, independent of
radiation effects, in that individuals with elevated hypoxia
treated by surgery alone have a worse outcome in terms of
loco-regional control and metastatic spread (Hockel et al.
1996). In an interesting approach it was shown that large frac-
tion sizes (>10 Gy) activate a rapid endothelial apoptotic
response via membrane located acid sphingomyelinase that
releases the pro-apoptotic compound, ceramide, and that
tumor cure with single-dose radiation was dependent on acti-
vation of this endothelial cell stress pathway (Fuks and
Kolesnick 2005). This raises the possibility that an initial large-
dose fraction could affect the response to subsequent fractions
via changes in tumor perfusion or hypoxia. Such effects are
subject to further modification including hypoxia triggered
elevation in HIF1α/IF1β that transcriptionally activates
VEGF—a proangiogenic factor, in addition to more broad
effects such as ATM/ATR-mediated cell cycle checkpoint
control and reduced ability to execute HR repair via suppres-
sion of RAD51 (Chan et al. 2008; Hammond et al. 2003).
Repopulation
In an early, but key, analysis of clinical data by Withers et al.
it was found that after approximately 3 weeks of treatment,
repopulation of tumor was observed that would require addi-
tional dose for control (Withers 1985). The continuous deliv-
ery of conventional fractionation to prevent treatment
prolongation was the empirical answer to keep this expan-
sion in check. In the case of SBRT and SRS, the expedited
delivery of a tumoricidal dose should mitigate any clonal

expansion, offering a significant advantage, particularly for
rapidly dividing tumors.
Redistribution
Both conventional and hypofractionated regimes will selec-
tively kill cells in the most sensitive part of the cell cycle,
G2/M, leaving a cohort of relatively resistant cells. Thus far it
has not proved possible to take advantage of this synchrony,
due to the presence of subpopulations of tumor cells that cycle
at different rates and the complexity of proactively measuring
the ideal time for subsequent irradiation. However, reducing
the number of fractions does alter the probability of irradiat-
ing a cohort of cells as they move into a radiosensitive phase.
Radiosensitivity
Tumor cells derived from radioresponsive tumors are more
radiation sensitive than those, such as glioblastoma, that are
harder to control (Malaise et al. 1987; Deacon et al. 1984).
However, though the differential radiosensitivity observed
between tumor types is significant at low (conventional frac-
tionation) doses, at high doses, in the exponential part of the
dose-response curve, no differential sensitivity is observed
(Malaise et al. 1987). Thus SRS/SBRT should mitigate differ-
ences in tumor kill that are directly attributable to variations in
individual tumor cell radiation sensitivity. Stem cells have
been identified in solid tumors of breast, brain, and elsewhere
(Al-Hajj et al. 2003; Singh et al. 2004). Such cells are notably
more radiation resistant, likely through enhanced DNA
repair secondary to increased CHK1/2 cell cycle checkpoint
function (Bao et al. 2006). The increased fraction size and
shorter treatment time of SRS/SBRT may provide less oppor-
tunity for the selection and outgrowth of resistant stem cells.
Cell Death
Assessment of radiation lethality is best demonstrated using
the clonogenic assay: single, viable cells divide five or six
times in culture forming a countable colony. Using this tool,
2. Radiobiology 15
the shape of the dose-response survival curve for most

human carcinoma cells exhibits an initial shoulder region, fol-
lowed by a simple exponential when plotted as log survival
against dose. This is a key feature in terms of estimating dif-
ferences in lethality between conventional vs. SRS/SBRT
treatments. For those cells that die, mitotic catastrophe is the
most frequent lethal route for carcinomas. In this route, two
chromosomes are fragmented by radiation and subsequently
fuse. If the derivative structure contains two centromeres (a
dicentric is one example) it may attach to both poles of the
mitotic spindle and physically restrict cell division, killing the
cell. Of the remainder, autophagy, necrosis, or senescence are
likely minor components of radiation lethality; autophagy
observed as sequestering of organelles, membrane, and cyto-
plasm into autophagosomes; necrosis releases cellular con-
tents triggering inflammation; and in senescence, cells stop
dividing, linked to an elevation in β [beta] galactosidase,
senescence-associated heterochromatin foci (SAHP), and
DNA fragmentation staining. However, a mitotic catastrophe
may trigger an apoptotic phenotype (nuclear fragmentation,
caspase 3 and 9 activation, elevation in bax, suppression of
bcl2) secondary to mitotic arrest (Surova and Zhivotovsky
2013). As noted above the higher doses of SRS/SBRT may
selectively trigger apoptosis in endothelial cells that may
impact tumor control (Table 2.1).
Models of Cell Survival

The linear quadratic (LQ) interpretation of cell survival
curves was developed in the conventional (non-IGRT) frac-
tionation era to estimate the response of tumors and late
reacting normal tissues to variations in fractionation sched-
ules (Eq. 2.1). Here the surviving fraction (SF) is related to
dose D through both linear and quadratic components:
SF = e -a D + b D 2 (2.1)
In its simplest form, differences in tissue or tumor responses

can be calculated using BED, the biologically effective dose,
obtained from a fraction size of dose d delivered n times
(Eq. 2.2). Average values of the α/β ratio are often taken as 3
(Gy3) for late reacting tissues, or 10 (Gy10) for acute responses,
including most tumors:
æ d ö
BED = nd ç 1 + ÷ (2.2)
è a /b ø
In the changing landscape provided by IGRT technology,

SRS/SBRT incorporates increased fraction sizes and better
tumor/normal tissue discrimination. This has led to inconsis-
tencies when trying to identify biologically equivalent doses
of conventional fractionation with that delivered by SRS/
SBRT.
The major issue is that the LQ formula describes a con-
tinuously bending dose-response curve (the βD2 component)
whereas what is most commonly observed is a simple expo-
nential response following an initial shouldered region. Thus
using Eq. (2.2) to predict the BED of an SRS/SBRT treat-
ment will potentially overestimate toxicity. A number of
models have been proposed that counter this discrepancy. Of
the many published models, the Universal Survival Curve
(USC) of Park et al. offers a direct approach and grafts a
multitarget dose-response model on to a standard LQ
equation (Park et al. 2008). This has the benefit of better rep-
resenting the biological reality of radiation lethality of simple
survival curves, but does not address the many differences in
clinical responses linked to SRS/SBRT that are discussed
above. Many in the field are still divided on the issue, some
suggesting that the LQ relationship is still valid, and others
being less convinced (Park et al. 2008; Guerrero and Li 2004;
Shibamoto et al. 2012). Sample calculations made using Eq.
(2.2) illustrate the dramatic differences in calculated BED
using the LQ formula for SRS/SBRT (Table 2.2). We would
offer the following guidance: To generate an indication of the
potency of a SRS/SRBT schedule compared to a conventional
2. Radiobiology 17
Table 2.1 Advantages and disadvantages of SRS/SBRT from a

radiobiological perspective, organized according to the five “R”
principles of radiobiology
SRS/SBRT SRS/SBRT advantage
Parameter disadvantage
Repair Limits the number of Improved tumor
cycles of damage and targeting reduces the
repair that separates dose to normal tissues
the tumor response and the need for sparing
from normal tissue by fractionation
toxicity
Reoxygenation Fewer treatment None
cycles potentially
reduces inter-fraction
reoxygenation
and thus increases
radioresistance
Repopulation None Much reduces or
eliminates tumor
repopulation during
shorter treatment—
specifically relevant to
radiation resistant tumor
stem cells
Redistribution Reduced numbers of fractions will affect the
cell cycle distribution of remaining viable cells.
Though redistribution could favor fractionated
RT which provides a higher probability of
catching cells in their vulnerable cell cycle
states, the clinical significance is unknown
Radiosensitivity None Multi-log cell kill reduces
the variability in tumor
radiosensitivity primarily
observed within the
shoulder region of the
cell survival curve. Single-
tumor doses >10 Gy may
trigger endothelial cell
apoptosis
Table 2.2 BED calculation

Schedule BED Gy3 BED Gy10
2 Gy × 30 72 100
20 Gy × 3 180 460
fractionation scheme, the LQ formula will provide appropri-

ate estimates up to fractional doses in the range of 6–10 Gy.
Above this, application of the LQ methodology will have
reduced power to provide a comparison with conventional
schedules. However, as in all applications of BED calculations,
the result generated should only be considered as a guide. In
the case of clinical questions related to normal tissue toxicity
from SRS/SBRT schedules, empirically established dose limits
and tolerances from relevant clinical literature should be
respected for this increasingly used modality.
References
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke
MF. Prospective identification of tumorigenic breast cancer cells.
Proc Natl Acad Sci U S A. 2003;100:3983–8.
Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, et al. Glioma stem cells
promote radioresistance by preferential activation of the DNA
damage response. Nature. 2006;444:756–60.
Chan N, Koritzinsky M, Zhao H, Bindra R, Glazer PM, et al. Chronic
hypoxia decreases synthesis of homologous recombination pro-
teins to offset chemoresistance and radioresistance. Cancer Res.
2008;68:605–14.
Deacon J, Peckham MJ, Steel GG. The radioresponsiveness of human
tumours and the initial slope of the cell survival curve. Radiother
Oncol. 1984;2:317–23.
Fuks Z, Kolesnick R. Engaging the vascular component of the tumor
response. Cancer Cell. 2005;8:89–91.
Guerrero M, Li XA. Extending the linear-quadratic model for large
fraction doses pertinent to stereotactic radiotherapy. Phys Med
Biol. 2004;49:4825–35.
2. Radiobiology 19
Hammond EM, Dorie MJ, Giaccia AJ. ATR/ATM targets are phos-

phorylated by ATR in response to hypoxia and ATM in response
to reoxygenation. J Biol Chem. 2003;278:12207–13.
Hockel M, Schlenger K, Aral B, Mitze M, Schaffer U, et al. Association
between tumor hypoxia and malignant progression in advanced
cancer of the uterine cervix. Cancer Res. 1996;56:4509–15.
Jackson SP, Bartek J. The DNA-damage response in human biology
and disease. Nature. 2009;461:1071–8.
Malaise EP, Fertil B, Deschavanne PJ, Chavaudra N, Brock
WA. Initial slope of radiation survival curves is characteristic of
the origin of primary and established cultures of human tumor
cells and fibroblasts. Radiat Res. 1987;111:319–33.
Park C, Papiez L, Zhang S, Story M, Timmerman RD. Universal sur-
vival curve and single fraction equivalent dose: useful tools in
understanding potency of ablative radiotherapy. Int J Radiat
Oncol Biol Phys. 2008;70:847–52.
Reddy SB, Williamson SK. Tirapazamine: a novel agent targeting
hypoxic tumor cells. Expert Opin Investig Drugs. 2009;18:77–87.
Rischin D, Peters LJ, O’Sullivan B, Giralt J, Fisher R, et al.
Tirapazamine, cisplatin, and radiation versus cisplatin and radia-
tion for advanced squamous cell carcinoma of the head and neck
(TROG 02.02, HeadSTART): a phase III trial of the Trans-Tasman
Radiation Oncology Group. J Clin Oncol. 2010;28:2989–95.
Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, et al.
Identification of human brain tumour initiating cells. Nature.
2004;432:396–401.
Shibamoto Y, Otsuka S, Iwata H, Sugie C, Ogino H, et al.
Radiobiological evaluation of the radiation dose as used in high-
precision radiotherapy: effect of prolonged delivery time and
applicability of the linear-quadratic model. J Radiat Res.
2012;53:1–9.
Surova O, Zhivotovsky B. Various modes of cell death induced by
DNA damage. Oncogene. 2013;32:3789–97.
Valdiglesias V, Giunta S, Fenech M, Neri M, Bonassi S. gammaH2AX
as a marker of DNA double strand breaks and genomic instabil-
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Withers HR. Biologic basis for altered fractionation schemes.
Cancer. 1985;55:2086–95.
Part II
Physics of Stereotactic
Body Radiotherapy
Chapter 3
Physics of Stereotactic
Body Radiotherapy
Angélica Pérez-Andújar, Martina Descovich,
and Cynthia F. Chuang
Pearls
High doses of radiation delivered over 1–5 fractions
(high biological effective dose).
High-precision radiation delivery techniques combin-
ing image guidance solutions and stereotactic coordi-
nate systems.
Very conformal dose distribution with steep dose
gradients.
A. Pérez-Andújar, PhD ()

San Francisco, 505 Parnassus Avenue, Suite L08-D, San Francisco,
CA 94143-0226, USA
e-mail: perezandujara@radonc.ucsf.edu
M. Descovich, PhD
San Francisco, Helen Diller Family Comprehensive Cancer Center,
Box 1708, 1600 Divisadero St, MZ Bldg R H1031, San Francisco,
CA 94143-1708, USA
C.F. Chuang, PhD
San Francisco- Mission Bay, 1825 4th Street Room M-1215,
San Francisco, CA 94158, USA

24 A. Pérez-Andújar et al.
Margin reduction, but consider that a large source of

uncertainty relates to target delineation.
Requires a rigorous quality assurance program and
end-to-end commissioning procedures incorporating
imaging, simulation, treatment planning, image guid-
ance, motion management, and treatment delivery
systems.
Basic Principles
Originally developed for the treatment of intracranial
lesions (Leksell 1983), radiosurgery is rapidly
evolving.
Both intracranial (SRS) and extracranial (SBRT)
treatment sites.
Recommendations for normal tissue dose tolerances
are reported in AAPM TG-101 (Benedict et al. 2010)
(Table 3.1).
Patient setup and immobilization devices vary depend-
ing on body site, treatment platform, and the capability
of the delivery system to detect and correct for
changes in patient position during treatment.
The stereotactic coordinate system is provided either
by an invasive fixation device (head frame) or by the
imaging system (frameless radiosurgery).
SRS: Stereotactic head frame attached to the
patient’s skull using pins (Khan 2003). Frameless
system could include thermoplastic mask with
reflective markers and vacuum-assisted
mouthpieces.
SBRT: body frames, body cast, and vacuum bags
(Table 3.2).
Imaging techniques for SRS/SBRT treatment
verification (Murphy et al. 2007; German et al. 2001;
Broderick et al. 2007; Li et al. 2008; Jin et al. 2008): 2D
MV electronic portal imaging (EPID).
Orthogonal kV radiographs.
MV cone beam CT.
3. Physics 25
Table 3.1 General comparison of conventional radiotherapy

treatment versus stereotactic therapy (SRS/SBRT)
Characteristic Conventional RT SRS/SBRT
Prescription ≤3 Gy ≥5 Gy
dose per fraction
Number of ≥10 ≤5
fractions
Dose Homogeneous (max Heterogeneous
distribution PTV dose ≈105–110 %) (max PTV dose
≈110–200 %)a
Dose gradient Shallow slope Steep slope
outside PTV
Prescription ≈90–95 % ≈50–95 %a
isodose line
Target definition Tumor might not have Well-delineated
a sharp boundary target
PTV margin ≈cm ≈mm

Modified from Linda Hong’s presentation (Benedict et al. 2010;
Hong 2012)
a
Heterogeneity of SRS/SBRT plans is highly dependent on the
treatment technique used. The same applies to the prescription
isodose lines
Table 3.2 Reported accuracy of commercially available SBRT

immobilization devices (Taylor et al. 2011)
Site System Reported accuracy (mm)
Lung Elekta body frame 1.8–5
MI body fix 2.5–3
Leinbinger body frame 2–4.4
Liver Elekta body frame ≤4.4
MI body fix ≤3.2
Leinbinger body frame 1.8–4.4
Spine MI body fix ≈1

Body cast ≈3
Fiducial marker tracking 2
kV cone beam CT.

MV helical CT.
In-room diagnostic CT.
4DCBCT.
Infrared imaging.
Radiofrequency tracking.
Management of respiratory motion for SBRT motion-
encompassing techniques (4DCT—ITV delineation).
Abdominal compression—this method reduces the
target excursion with breathing.
Breath-hold—radiation is delivered when the patient
is holding the breath.
Gating—radiation is delivered only at a particular
phase of respiration.
Dynamic target tracking—beams are re-targeted in
real time to the continuously changing target posi-
tion—advantages: no need for ITV expansion; no
treatment interruptions; accounts for changes in target
motion and respiratory pattern during treatment.
SRS/SBRT Treatment Parameters
Target volumes: The concept of GTV, CTV, PTV, and
ITV described in ICRU 50 and 62 for SRS also applies
to SBRT planning (Medin et al. 2010; ICRU 1993).
PTV margins depend on body site, treatment device,
localization technique, and imaging frequency. Typical
margins range from 2 to 5 mm for SBRT.
Dose conformity: the high-dose volume conforms
tightly around the target.
Dose heterogeneity: hot spots located within the tar-
get are often considered not only acceptable, but also
desirable. The prescription dose is typically 50–90 % of
the maximum dose depending on the treatment deliv-
ery and treatment planning systems.
Dose gradient: the dose fall-off away from the target is
steep. The volume of normal tissue receiving high doses
of radiation is kept at a minimum. This is in comparison
with other treatment techniques like 3D conformal.
3. Physics 27
Beam energy: 6 MV photons offer the best compro-

mise between beam penetration and penumbra char-
acteristics. Many techniques use unflattened beams.
Beam shaping: Radiation is collimated to a small field
using heavy metal cones (circular field 4–60 mm diam-
eters), multileaf collimator (MLCs), or microMLCs
(2.5 mm leaves width). MLCs and micro MLCs are
used to deliver treatments developed with conformal
beams, intensity modulated fields, dynamic conformal
arcs, or a combination of these (ICRU 1999).
Treatments are delivered via coplanar and non-copla-
nar beam arrangements.
Circular fields provide a sharper penumbra than
microMLCs.
Beam geometry: multiple non-overlapping beams con-
centrically pointing to the target; 5–12 coplanar or
non-coplanar beams; 1 or 2 coplanar or non-coplanar
arcs; a continuously rotating fan beam; hundreds of
non-coplanar pencil beams pointing to different parts
of the target (non-isocentric beam arrangement) or to
the same point (isocentric beam arrangement).
Plan Optimization
Forward planning: the user manually adjusts beam
arrangement, field shapes, and weights until the desir-
able dose distribution is achieved.
Inverse planning: the user specifies plan objectives for
target and normal structures and a dose optimization
algorithm calculates field shapes and weights based on
the minimization of a mathematical cost function.
Plan Classification
3-Dimensional conformal radiation therapy (3D-
CRT): typically forward planned. It might be advanta-
geous for moving targets, as the target is always in the
open radiation field.
Intensity-modulated radiation therapy (IMRT): typi-
cally inverse planned (although the field-in-field tech-
nique is forward planned).
Arc therapy (RapidArc, VMAT).
Dose Calculation Algorithms

Pencil beam algorithms using radiological path length
corrections to account for tissue heterogeneities. Not
accurate in conditions of electronic disequilibrium. In
these cases, heterogeneity corrections explicitly
accounting for the transport of secondary electrons
must be employed. While the most accurate technique
for dose calculation is Monte Carlo, convolution-
superposition methods are sufficiently accurate in
most clinical situations.
Calculation grid: should be less than 2 × 2 × 2 mm3.
Treatment Platforms and Cross-Platform

Comparisons
SRS/SBRT treatments can be performed using a vari-
ety of devices producing X rays, gamma rays or parti-
cle radiation (Tables 3.3 and 3.4) (Combs et al. 2012;
Dieterich and Gibbs 2011; Soisson et al. 2006):
Robotic linac radiosurgery system (CyberKnife).
Helical TomoTherapy.
Gamma Knife.
Other linac-based systems.
Quality Assurance and Patient Safety

AAPM Task Group 101, Section VII.B. states that
“Specific tests should be developed to look at all
aspects of the system both individually and in an inte-
grated fashion (Benedict et al. 2010).”
Systematic treatment accuracy verification is
required for
CT/MR imaging.
Fusion uncertainties.
Planning calculation.
Table 3.3 Characteristics of various platforms for SRS/SBRT
Technology Delivery system Radiation Dose rate Beam shaping
CyberKnife Compact linac 6 MV unflattened Up to 1000 MU/ 12 Interchangeable
mounted on a photon beam min tungsten cones;
robotic arm variable aperture
collimator; MLC
(not yet clinically
available)
Tomotherapy Helical, CT-like 6 MV unflattened ~850 cGy/min at Binary MLC (64
gantry equipped with photon beam isocenter leaves, 0.625 cm wide)
a linac waveguide
Gamma knife 192 (Perfexion) or 1.17 and 1.33 MeV Initial source Tungsten barrel
201 (models B-4C) gamma rays activity ~6000 Ci, subdivided into 8
60
Co sources dose-rate at focal sectors (Perfexion);
point >3 Gy/min 4 interchangeable
helmets (models
B-4C)
3.
Linac-based Gantry-based linac Multiphoton 600 MU/min up to MLC with standard

systems rotating about the energies (6, 10, 15, 2400 MU/min (5 mm width) or
isocenter 18 MV-flattened and micro (2.5 mm width)
Physics
unflattened) and leaves

electron energies
29
(continued)
30
Table 3.3 (continued)

Technology Field sizes Beam arrangements Treatment time
CyberKnife Circular fields: Hundreds of non- Long (20 min–1.5 h)
5–60 mm diameter coplanar beams. No
posterior beams
Tomotherapy Max field length Treatments are Short (15–30 min)
40 cm. Slices widths delivered by
of 1, 2.5 and 5.0 cm synchronization of
gantry rotation, couch
A. Pérez-Andújar et al.
translation, and MLC

motion
Gamma knife 4, 8 and 16 mm Multiple isocenters Long (hours)
(Perfexion); 4, 8, (shots)
14, 18 mm (models
B-4C)
Linac-based Standard MLC Multiple isocentric Fast (15–30 min)
systems typically gives a beams; coplanar or
40 × 40 field, micro- non-coplanar beams;
MLC gives a smaller coplanar or non-
field (12 × 14 cm2) coplanar arcs
Table 3.4 IGRT solutions
Technology Imaging system Imaging frequency Image registration algorithms Motion management
CyberKnife 2D orthogonal Every 15–150 s Automatic registration of Synchrony
X-ray images at (typically 30–60 s) live camera images with respiratory motion
45° DRR using site specific tracking
algorithms (skull, fiducial,
spine, lung)
TomoTherapy 3D MVCT Prior to each Automatic registration None
treatment of MVCT with planning
CT based on bony and/
or soft tissue anatomical
landmarks
Linac-based 2D kV or MV Depending on Automatic registration of Gated delivery
systems images, 2D imaging modality CBCT with planning CT verified by 2D real-
(Varian- fluoroscopy, prior or during using either bony anatomy time fluoroscopic
3.
TrueBeam, 3D kV CBCT, treatment or soft tissue information. imaging or 4D CBCT

Elekta-Versa) 3D ultrasound, 3D ultrasound images
infrared system are also automatically
co-registered to the
Physics
planning CT
31
Target localization.
Dose delivery.
This section focuses on target localization, IGRT system
quality assurance, and dosimetry quality assurance.
Target Localization Accuracy
A top priority for SBRT/SRS treatments.

The standard for dosimetric target localization accu-
racy is the “Winston-Lutz” test or a similar test for
frameless SRS/SBRT procedures (Medin et al. 2010;
Solberg et al. 2008).
Patient treatment target localization is achieved with
either stereoscopic localization X-rays or CBCT for
the Cyberknife and the linac-based systems, and with
stereotactic head frames for GK.
IGRT System Quality Assurance
Daily imaging isocenter check and simple localization

check should be done daily when SBRT treatments
are to be performed.
IGRT Imaging Systems
Both kV-CBCT and MV-CBCT systems need:

To calibrate for proper registration of the treatment
beam isocenter.
To correct for accelerator and imaging component
sags and flexes.
To certify the geometric accuracy of the imaged-
guided procedures (Bissonnette 2007; Bissonnette
et al. 2008).
AAPM Task Group 142 on QA of Medical Accelerators,
Table VI recommends QA tasks tolerance and
3. Physics 33
frequency for both planar and cone beam images. They

include:
Safety and functionality.
Geometrical accuracy:
Imager isocenter accuracy.
2D/2D match, 3D/3D registration accuracy.
Image magnification accuracy.
Imager isocenter accuracy with gantry rotation.
Image quality:
Contrast resolution and spatial resolution.
Hounsfield Units linearity and uniformity.
In-slice spatial linearity and slice thickness
(Klein et al. 2009).
For a detailed list of the recommended tests and toler-
ances the reader is referred to TG-142.
IGRT Couch Shift Accuracy
Need to verify the accuracy of the robotic couch
movement.
To ensure proper operation of the IGRT device and
workflow.
To assess communication between the image regis-
tration software and the remote-controlled couch.
Is determined using the “residual correlation error”
method (for details, please refer to TG-179).
This value should be near 0 ± 2 mm, according to
TG-179 (Bissonnette 2007).
Dosimetric Quality Assurance
Validation measurement vs. treatment planning output

Validation measurements need to be conducted after
commissioning of the treatment planning system (TPS)
and before the start of SRS/SBRT programs.
These ensure that the TPS is calculating the correct
dose, and that the IGRT imaging system and the track-
ing/delivery system are delivering accurately.
Measurements Include
Simple square field and/or circular cone outputs.
Percent depth dose (PDD) and energy measure-
ments compared with treatment planning
calculations.
Simple 3D plans and some IMRT plans should be
planned, delivered, and measured to verify the dose
calculation and delivery accuracy.
Measurements should cover the whole range of possi-
ble field sizes, and different tracking methods (i.e., kV
imaging, cone beam, and for CK, different track
algorithms).
When treating multiple sites, double or multiple isocen-
ter plans would need to be verified.
Special care should be taken to verify small field dosim-
etry during these SRS/SBRT end-to-end validation
tests, since this particular area is most prone to commis-
sioning inaccuracy and also to dose planning
uncertainty.
Routine Quality Assurance Program

Routine quality assurance measurements are needed
once the SRS/SBRT program has started, to ensure the
continuing dosimetry accuracy for these treatments.
Beam stability test:
The output and energy of the beam should be
checked daily (Table 3.5).
Tighter tolerance (constancy and accuracy to the
sub mm) is needed for SBRT/SRS treatments
delivered using micro-MLC or high-definition
MLC (Klein et al. 2009).
For Cyberknife robotic radiosurgery, TG-135 on
“Quality assurance for robotic radiosurgery”
recommends individual component QA and
overall system QA, with specific daily, monthly,
and annual frequency and tolerance tables in
IVB, C and D.
3. Physics 35
End-to-end test: Including motion tracking/gating

end-to-end test.
Each individual component of the SRS/SBRT
process (imaging, localization, treatment deliv-
ery, etc.) has associated errors.
The cumulative system accuracy needs to be
characterized through an end-to-end test using
phantoms with measurement detectors and
imaging on a routine basis.
For the CyberKnife system, an end-to-end test is
conducted once a month, rotating among the dif-
ferent imaging/tracking modalities. Every month,
one end-to-end will be done for the fixed cone
and one for the Iris.
The end-to-end tests have to be repeated every
time there is an upgrade to the system for all
modalities.
Depending on the treatments, end-to-end tests
could be done at the physicists’ discretion to best
reflect the delivery/imaging modalities used.
Patient-specific QA.
Per TG-101, treatment-specific and patient-
specific QA procedures should be established to
govern both the treatment planning and delivery
process as a whole, as well as to provide a sanity
check of the setup.
For a new SRS/SBRT program, frequent patient-
specific QA should be conducted until the physi-
cist in charge is confident of the delivery accuracy
of the modality.
Extremely small fields warrant patient specific QA for
all plans, since these cases involve both potential mea-
surement uncertainty and positioning uncertainty:
The output factors measured carry certain uncer-
tainties (cones <7.5 mm and MLC fields <1 × 1 cm).
MicroMLC or IRIS positioning uncertainties,
examples:
Cyberknife: IRIS 10 mm or lower.
For linac-based SRS/SBRT using micro-MLCs:
any field size less than 1 cm.
Table 3.5 Daily, monthly, and annual tests for SRS and SBRT
systems (recommendations based on TG-142) (Klein et al. 2009)
Daily QA
Mechanical tests Tolerance
Laser localization 1 mm
Distance indicator (ODI) 2 mm
@ iso
Collimator size indicator 1 mm
Monthly QA
Dosimetry tests Tolerance
Typical dose rate output 2 % (@ stereo dose rate, MU)
constancy
Mechanical tests Tolerance
Treatment couch position 1 mm/0.5°
indicators
Localizing lasers <±1 mm
Annual QA
Dosimetry tests Tolerance
SRS arc rotation mode Monitor units set vs. delivered:
(range: 0.5–10 MU/deg) 1.0 MU or 2 % (whichever is
greater)
Gantry arc set vs. delivered: 1.0°
or 2 % (whichever is greater)
X-ray monitor unit ±5 % (2–4 MU)
linearity (output ±2 % ≧5 MU
constancy)
Coincidence of radiation ±1 mm from baseline
and mechanical isocenter
Stereotactic accessories, Functional

lockouts, etc.
3. Physics 37
Need to use equipment that has the correct resolu-

tion for QA, i.e., film for isodose distribution, and
either pinpoint chamber or diode for absolute mea-
surement to avoid any volume averaging issues.
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Kavanagh B, et al. Stereotactic body radiation therapy: the report
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Combs SE, Ganswindt U, Foote RL, Kondziolka D, Tonn JC. State-
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Dieterich S, Gibbs IC. The CyberKnife in clinical use: current roles,
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et al. Advances in 4D medical imaging and 4D radiation therapy.
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Soisson ET, Tome WA, Richards GM, Mehta MP. Comparison of
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Part III
Clinical Applications
Chapter 4
Intracranial Tumors
David R. Raleigh, Igor J. Barani, Penny Sneed,
and David A. Larson
Pearls
Brain Metastases
Most common intracranial tumor (20–40 % of all

cancer patients on autopsy); most often from lung
cancer, breast cancer, or melanoma.
“Solitary” metastasis: one brain lesion as the only site
of disease; “single” metastasis: one brain metastasis,
other sites of disease.
Start dexamethasone up to 4 mg q6hrs for neurologic
symptoms; no role for steroids in asymptomatic patients.
Taper as tolerated once radiotherapy is complete; no
evidence for seizure prophylaxis (Table 4.1).
D.R. Raleigh • P. Sneed

1600 Divisadero Street, Basement Level, San Francisco,
CA 94143-1708, USA
I.J. Barani • D.A. Larson ()
University of California, San Francisco, 1600 Divisadero Street,
Basement Level, San Francisco, CA 94143-1708, USA
e-mail: DLarson@radonc.ucsf.edu

42 D.R. Raleigh et al.
Table 4.1 RTOG RPA for brain metastases (Gaspar et al. 1997)
Survival
Class Characteristics (months)
I KPS 70–100 7.1
Age <65
Primary tumor controlled
Metastases to brain only
II All others 4.2
III KPS <70 2.3
Table 4.2 Simpson grading system for meningioma resection

Grade I Macroscopic complete removal with excision
of dural attachment, any abnormal bone, and
involved venous sinus(es)
Grade II Macroscopic complete removal with coagulation of
dural attachment
Grade III Macroscopic complete removal of intradural
component(s), without resection or coagulation of
dural attachment or extradural extensions
Grade IV Partial removal with residual intradural tumor in
situ
Grade V Simple decompression with or without biopsy
Meningioma
Thirty-percent of primary intracranial neoplasms; two-

fold more likely in women (although incidence is equal
for anaplastic meningiomas) and linked to ionizing
radiation, viral infection, sex hormones, NF2, and loss of
chromosome 22q (Table 4.2).
Acoustic Neuroma
Acoustic neuromas (i.e., vestibular schwannomas)

arise from myelin sheath Schwann cells surrounding
the vestibular nerve; 6–8 % of intracranial tumors,
overall incidence ~1 % on autopsy studies.
4. Intracranial Tumors 43
Risk factors include acoustic trauma and coincidence

with parathyroid adenoma; bilateral acoustic neuro-
mas pathopneumonic for NF2.
Both CN VII and VIII may be affected (hearing loss,
tinnitus, vertigo, and unsteady gait), and extension into
the cerebellopontine angle may lead to dysfunction of
CN V (trigeminal pain) and the facial nerve (facial
paresis and taste disturbances), as well as compression
of the posterior fossa (ataxia, hydrocephalus, and death).
Mean growth rate ~2 mm per year, although may
remain stable for years.
Paraganglioma
Rare neuroendocrine tumors with incidence of

~1:1,000,000; sometimes called glomus tumors or che-
modectomas as they arise from glomus cells which
function as chemoreceptors along blood vessels.
Can occur in the abdomen (85 %), thorax (12 %), and
the head and neck (3 %); usually benign (<5 % malig-
nant potential).
Pituitary Adenoma
Approximately 10 % of intracranial tumors (5–25 %

incidence on autopsy), almost all of which arise in the
anterior lobe; 75 % functional (30–50 % prolactinoma,
25 % GH, 20 % ACTH, and <1 % TSH).
Microadenoma <1 cm; macroadenoma ≥1 cm.
Presenting symptoms include headaches, hydrocepha-
lus from 3rd ventricle obstruction, cranial nerve pal-
sies with extension to the cavernous sinus, and
bitemporal hemianopsia and/or loss of color discrimi-
nation from optic chiasm compression.
Forbes-Albright syndrome from prolactinoma:
amenorrhea-galactorrhea in women, impotence and
infertility in men.
Both mass effect and radiation damage to the pituitary

infundibulum can cause an elevation in prolactin due
to loss of hypothalamic inhibition (“stalk effect”).
Hormone levels typically normalize within 1–2 years
after radiotherapy.
Arteriovenous Malformation (AVM)
Abnormal congenital communication between arterial

and venous vasculature at a “nidus”; supraphysiologic
hydrodynamic gradient.
Low incidence in the US population (0.14 %), but 8 %
coincidence with cerebral aneurysm.
Annual rate of spontaneous hemorrhage ~2–6 %, with
morbidity 20–30 % and mortality 10–15 % per event;
after angiographic obliteration, lifetime risk of hemor-
rhage ≤1 %.
SRS induces vascular wall hyperplasia and luminal
thrombosis, but requires several years to achieve full
effect.
AVMs differ from cavernous malformations insofar as
the latter are composed of sinusoidal vessels without a
large feeding artery, and therefore have a low-pressure
gradient (Table 4.3).
Table 4.3 Spetzler–Martin AVM grading system (1–5)

Size of nidus <3 cm = 1
3–6 cm = 2
>6 cm = 3
Location Adjacent to non-eloquent brain = 0
Adjacent to eloquent cortex = 1
Venous drainage Superficial = 0
Deep = 1
Neuropathic Facial Pain
Trigeminal Neuralgia
CN V sensory nucleus disorder resulting in episodic,
provokable (i.e., shaving, brushing teeth, wind, etc.),
paroxysmal, unilateral, severe, lancinating pain lasting
seconds to minutes in the distribution of the trigeminal
nerve.
Predominantly idiopathic, although may be the result
of trigeminal nerve compression by an aberrant artery
or vein, or demyelination in multiple sclerosis.
Secondary trigeminal neuralgia due to mass effect
from meningioma, vestibular schwannoma, AVM,
aneurysm, or other lesions.
Diagnosis of exclusion; obtain MRI to rule out cere-
bellopontine angle neoplasm.
Median time to pain relief after SRS is ~1 month;
50–60 % CR, 15–20 % PR; <10 % incidence of facial
numbness after treatment.
Cluster Headache
Sudden onset of unilateral pain typically along the
distribution of CN V1; associated with ipsilateral auto-
nomic activity including ptosis, meiosis, lacrimation,
conjunctival injection, rhinorrhea, and nasal
congestion.
Etiology unclear; 6:1 male to female predominance.
GKRS to the trigeminal nerve alone not successful,
and is associated with much higher rate of toxicity than
during SRS for trigeminal neuralgia (Donnet et al.
2006; McClelland et al. 2006). Investigation of SRS to
the pterygopalatine ganglion +/− trigeminal nerve root
is ongoing (Kano et al. 2011; Lad et al. 2007).
Sphenopalatine Neuralgia (Sluder’s Neuralgia)
Rare craniofacial pain syndrome with 2:1 female pre-
dominance associated with unilateral pain in the orbit,
mouth, nose and posterior mastoid process as well as
ipsilateral autonomic stimulation from vasomotor
activity.
Etiology unclear; perhaps related to pterygopalatine

ganglion irritation from inflammation/infection of the
sphenoid or posterior ethmoid sinuses.
Radiosurgical data limited to case reports of sphenopala-
tine ganglion treatment (Pollock and Kondziolka 1997).
Other
Small retrospective series of SRS for residual/recur-

rent pineal parenchymal tumors, craniopharyngiomas,
and neurocytomas with high long-term local control
and survival.
SRS used as salvage treatment for certain functional
disorders, including epilepsy, Parkinson disease, and
essential tremor with varying efficacy.
Stereotactic treatment of residual/recurrent glial
tumors, medulloblastoma, and other aggressive CNS
malignancies has been reported, but outcomes are
discouraging. Hypofractionation of recurrent glial
tumors effective as salvage.
Treatment Indications
In general, SRS+WBRT is associated with longer sur-
vival than WBRT alone in patients with single metasta-
ses and KPS ≥70, improved LC and KPS preservation
in patients with 1–4 metastases and KPS ≥70, and
potentially, improved survival in patients with KPS <70.
SRS alone may provide equivalent survival and LC,
plus improved neurocognitive outcomes when com-
pared to SRS+WBRT or WBRT alone in patients with
≤3 metastases; close surveillance and salvage treat-
ment is essential.
After resection, both SRS+WBRT and WBRT alone
are acceptable adjuvant strategies, although SRS alone
may be used in select cases with minimal intracranial
disease and close surveillance (Linskey et al. 2010)
(Tables 4.4 and 4.5).
Table 4.4 Radiosurgical treatment indications for brain

metastases
Single lesion Surgical resection + SRS
to cavity
RPA class I–II SRS alone for medically/
surgically inoperable cases
2–4 Lesions SRS +/− surgical
RPA class I–II resection with excellent
prognosis/KPS
KPS ≤60, extensive intracranial/ WBRT
extracranial disease, and in
combination with SRS as
described above
Table 4.5 Radiosurgical treatment indications for benign intra-

cranial neoplasms
Meningioma Recurrent/residual disease after surgery
Recurrent disease after prior SRS/RT
Medically or surgically inoperable
Acoustic STR (LF 45 % without adjuvant RT vs. 6 %
neuroma with postoperative SRS)
Patient desire for greater preservation of
useful hearing (30–50 % with surgery)
Pituitary Adjuvant therapy after STR of
adenoma macroadenoma with persistent post-
operative hypersecretion or residual
suprasellar extension
Consider medical management with
bromocriptine or cabergoline for prolactin-
secreting microadenoma
AVM Medically inoperable, surgically inaccessible,
or anticipated high morbidity due to
Spetzler–Martin grade
Neurofacial Failure of medical management
pain (carbamazepine, phenytoin, gabapentin,
baclofen, etc.)
Failure of surgical management
(radiofrequency rhizotomy, balloon
compression, microvascular decompression,
etc.)
Workup
H&P with emphasis on neurologic components
Review of systems including any sensory changes, neu-
rologic symtpoms, and endocrine abnormalities.
Laboratories:
No routine serum tests necessary for the evaluation
of brain metastases, meningioma, AVM, neurofacial
pain syndromes, etc.
Acoustic neuroma: Audiometry is the best initial
screening, and typically shows sensorineural hear-
ing loss (as will the Rinne and Weber tests).
Pituitary adenomas: Endocrine evaluation with
prolactin, basal GH, serum ACTH, free cortisol,
dexamethasone suppression, TSH, T3, T4, FSH, LH,
plasma estradiol, and testosterone levels.
Imaging:
Thin-cut MRI with T1 pre- and post-gadolinium, T2,
and FLAIR (fluid attenuation inversion recovery)
sequences; tumor enhancement after gadolinium cor-
relates with breakdown of the blood-brain barrier,
abnormal T2 signal indicative of gliosis and/or edema.
Can consider increased dose gadolinium at the time
of radiosurgery to improve sensitivity of detection
of brain metastases.
Hemorrhagic metastases most often seen with renal
cell cancer, choriocarcinoma, and melanoma.
Magnetic resonance spectroscopy: tumors charac-
terized by increased choline (cellularity marker),
decreased N-acetylaspartic acid (NAA; neuronal
marker), and decreased creatinine (cellular energy
marker); necrosis associated with increased lactate
(anaerobic metabolism), and decreased choline/
NAA/creatinine.
Dynamic magnetic resonance perfusion: relative
cerebral blood flow (CBV) elevated in tumors
(often in concert with grade), and decreased in
areas of radiation necrosis and tumefactive
demyelination.
Post-operative MRI should be performed within 48

h of surgery to document residual disease; acute
blood appears as increased intrinsic T1 signal
pre-contrast.
“Dural tail sign” can be indicative of either tumor
extension or vascular congestion associated with
tumors adjacent or intrinsic to the meninges (seen
with 60 % of meningiomas).
Meningiomas are isointense on T1 and T2, and
intensely enhance with gadolinium; evidence of
bony destruction or hyperostosis in 15–20 % of
cases. Acoustic neuroma: Seen as enhancing “ice
cream cone” in the internal acoustic canal or as
“dumbbell” projecting into the foramen magnum.
Pituitary adenomas: X-ray skeletal survey should
be performed in cases of acromegaly to evaluate
growth plates
AVM: Co-registration of cerebral angiography and
time of flight MRI sequences helpful for target
delineation.
Neuropathic facial pain: Thin slice (1 mm)
MRI/MRA has sensitivity and specificity of 89 and
50 %, respectively, for identifying vascular compres-
sion of the trigeminal nerve.
Radiosurgical Technique
Simulation and treatment planning.
Simulation with stereotactic frame in place.
Primary MRI planning with thin cuts (1–2 mm)
preferred for intracranial radiosurgery, with fusion
of preoperative scans if available.
If necessary, CT slices no thicker than 2 mm should
be obtained and co-registered with MRI images.
Target volumes:
Brain metastases: GTV alone for intact lesions.
For resection cavities, a 1–2 mm margin may
increase local control (Soltys et al. 2008).
Meningioma, acoustic neuroma, pituitary ade-

noma, and other benign intracranial tumors:
GTV with 0–2 mm margin depending on degree
of immobilization and stereotaxis.
Trigeminal neuralgia: Target ipsilateral trigemi-
nal nerve adjacent to the pons in the retrogasse-
rian cistern with a single, 4 mm shot. Retreatment
isocenter should be located 2–3 mm away from
initial target if possible.
Dose prescription: See Table 4.6.
Consider hypofractionation in select cases if dose
constraints to critical structures cannot be met with
single-fraction treatment.
Dose delivery.
Multiple treatment modalities available, but most
centers employ GK SRS, frameless robotic radio-
surgery, and/or linac-based SRS.
Toxicities and Management

Stereotactic frame:
Mild headache immediately following frame
removal, usually subsiding within 60 min.
Minimal bleeding from pin insertion sites requiring
compression.
Peri-orbital edema resolving with head elevation
and warm compress.
<1 % Risk of superficial skin infection.
Acute (1 week to 6 months):
Alopecia and skin changes following treatment of
superficial lesions.
Mild fatigue.
Transient worsening of neurologic symptoms due to
edema potentially requiring steroids.
Late (>6 months):
Radiation necrosis: Overall five-percent rate of symp-
tomatic brain necrosis after SRS; typically resolves
with steroids, but may require surgical intervention.
Table 4.6 Dose recommendations and outcomes for intracranial

stereotactic radiosurgery
Presentation Recommended dose Outcomes
Brain 13–24 Gy/1 fraction
metastases depending on tumor
volume/location
Dosereduction or
hypofractionation
(21–30 Gy/3–5 fractions)
with larger lesions
and/or resection cavities
Consider dose
reduction (16 Gy) for
brainstem lesions
Meningioma Individualize dose
based on tumor volume/
location/surgical/
radiosurgical history
15 Gy/1 fraction Long-term LC
for WHO grade >90 % for WHO
I–III lesions; grade I lesions
hypofractionation to
25–30 Gy/5 fractions
possible, although long-
term results unknown
(UCSF experience).
Grade III lesions may
require higher dose
Acoustic 12–13 Gy/1 fraction LC and
neuroma preservation
of CNs V and
VII in excess of
95 %; hearing
preservation
~75 %
18–25 Gy/3–5 fractions Appears safe and
effective, but long-
term results are
unknown
Paraganglioma 15 Gy/1 fraction or LC ~100 %
hypofractionation to 25
Gy/5 fractions
(continued)

Presentation Recommended dose Outcomes
Pituitary Nonfunctioning tumors:
adenoma 12–20 Gy/1 fraction
Functioning tumors:
15–30 Gy/1 fraction
(maximal safe dose);
discontinue medical
therapy 4 weeks prior
to radiosurgery.
Single fraction optic
apparatus tolerance:
8 Gy
21–25 Gy/3–5 fractions Appears safe
and effective, but
long-term results
unknown
AVM Individualize dose 2-Year obliteration
based on tumor volume; rate for single-
staged radiosurgery for fraction treatment:
larger lesions <2 cm 90–100 %,
>2 cm 50–70 %
18 Gy/1 fraction for
8 cm3 target(s); dose
escalation when feasible
and safe (UCSF
experience)
Trigeminal Primary: 70–90 Gy (100 Pain relief in
neuralgia % isodose line) ~30–80 % of
patients, although
retreatment
common; dose
related to both
relief from
symptoms and
development of
new symptoms
Retreatment: 50–70 Gy
(100 % isodose line)
Pineal tumors Fractioned neuraxial
RT for high-grade
lesion; 15 Gy SRS
reserved for residual
tumor or local
recurrence after RT
Endocrine abnormalities.
Cranial nerve dysfunction following treatment of
skull base tumors.
Rare: memory impairment and cavernous
malformations.
Isolated case reports of stroke, facial palsy/
hyperesthesia, vision loss, and eye dryness after
SRS for trigeminal neuralgia, all of which are very
rare.
Recommended Follow-Up
Brain metastases and other high-grade lesions:
MRI 4–12 weeks after treatment, then every 2–3
months for the first 2-years, followed by imaging
every 6 months for the next 3 years, and yearly
thereafter; imaging intervals should be individual-
ized according to clinical symptoms and lesion
trajectory.
Low-grade lesions (meningioma, acoustic neuroma,
paraganglioma, etc.):
MRI every 6–12 months for the first 2-years, then
annually; imaging intervals should be individualized
according to clinical symptoms and lesion
trajectory.
Pituitary adenoma and other peri-sellar lesions:
Endocrine testing every 6–12 months with visual
field testing annually.
Acoustic neuromas and cerebellopontine angle tumors:
Formal audiometry annually.
AVM:
MRI up to once per year for 3 years after
treatment, with angiogram to confirm response
after 3 years.
Neuropathologic facial pain and functional disorders:
Clinical follow-up only.
Evidence
Brain Metastases
SRS Boost with WBRT
RTOG 95-08 (Andrews et al. 2004): Randomized,

multi-institution trial including 333 patients with 1–3
brain metastases and KPS ≥70 treated with WBRT
(37.5 Gy/15 fractions) plus SRS (15–24 Gy/1 fraction)
vs. WBRT alone. Significant survival advantage with
SRS in patients with a single metastasis on univariate
analysis (6.5 vs. 4.9 months), RPA class I on multivari-
ate analysis (11.6 vs. 9.6 months), and trends for advan-
tage with lung histology (5.9 vs. 3.9 months), and
tumor size >2 cm (6.5 vs. 5.3 months). WBRT+SRS
also associated with significantly higher 1-year LC (82
% vs. 71 %), and improved KPS (13 % vs. 4 %) with
decreased steroid use at 6 months. Minimal acute- and
long-term toxicity.
University of Pittsburgh (Kondziolka et al. 1999a, b):
Randomized trial of 27 patients with 2–4 brain metas-
tases and KPS ≥70 treated with WBRT (30 Gy/12 frac-
tions) plus SRS (16 Gy/1 fraction) vs. WBRT alone.
Study stopped early due to significant interim benefit
in LC for WBRT+SRS (100 % vs. 8 %); median time
to LF 6 months with WBRT vs. 36 months with
WBRT+SRS. No difference in OS (8 vs. 11 months),
and survival equal (~11 months) when accounting for
SRS salvage in WBRT arm. No difference in OS or LC
depending on histological type, number of brain metas-
tases, or extent of extracranial disease.
SRS Alone or With WBRT
RTOG 90-05 (Shaw et al. 2000): Dose escalation study

including 156 patients (36 % recurrent primary brain
tumors, median prior dose of 60 Gy; 64 % recurrent
brain metastases, median prior dose of 30 Gy).

Maximum tolerated doses of 24 Gy, 18 Gy, and 15 Gy
for tumors ≤ 20 mm, 21–30 mm, and 31–40 mm in
diameter, respectively; MTD for tumors <20 mm likely
higher, but investigators reluctant to escalate further.
Tumor diameter ≥2 cm significantly associated with
increasing risk of grade ≥3 neurotoxicity on multivari-
ate analysis; higher dose and KPS also associated with
greater neurotoxicity. Actuarial 24-month risk of
radionecrosis 11 %. Patients with primary brain tumors
and those treated on linear accelerators (as opposed to
GKRS) had ~2.8-fold greater chance of local
progression.
JROSG 99-1 (Aoyama et al. 2006): Randomized,
multi-institution trial including 132 patients with 1–4
brain metastases (diameter <3 cm) and KPS ≥70,
treated with SRS (18–25 Gy/1 fraction) vs. WBRT (30
Gy/10 fractions) followed by SRS. Trial stopped early
due to low probability of detecting a difference
between arms. Addition of WBRT reduced rate of new
metastases (64 % vs. 42 %) and need for salvage brain
treatment, and improved 1-year recurrence rate (47 %
vs. 76 %). No difference in OS (~8 months), neurologic
or KPS preservation, or MMSE score.
MDACC (Chang et al. 2009): Randomized trial includ-
ing 58 patients with 1–3 brain metastases and KPS ≥70
treated with SRS (15–24 Gy/1 fraction) vs. SRS+WBRT
(30 Gy/12 fractions) and followed with formal neuro-
cognitive testing. Trial stopped early due to significant
decline in memory and learning at 4 months with
WBRT by Hopkins Verbal Learning Test (52 % vs. 24
%). However, WBRT also associated with improved
LC (100 % vs. 67 %) and distant brain control (73 %
vs. 45 %) at 1 year. Significantly longer OS with SRS
alone (15 vs. 6 months), but patients in this arm
received more salvage therapy including repeat SRS
(27 vs. 3 retreatments).
UCSF (Sneed et al. 1999): Retrospective review of

GKRS (n = 62) vs. GKRS+WBRT (n = 43); treatment
characteristics individualized according to physician
preference. OS (~11 months) and 1-year local FFP (71
% vs. 79 %) equivalent. Although brain FFP signifi-
cantly worse for SRS alone (28 % vs. 69 %), no differ-
ence when allowing for first salvage (62 % vs. 73 %)
after 1 year.
Sneed et al. (2002): Retrospective, multi-institution
review of 569 patients with brain metastases treated
with SRS alone (n = 268) vs. WBRT+SRS (n = 301);
exclusion criteria included resection of brain metasta-
sis and interval from end of WBRT to SRS >1 month.
Median and overall survival no different among
respective RPA statuses (I: 14 vs. 15 months; II: 8 vs. 7
months; class III: ~5 months). Twenty-four percent
WBRT salvage rate in SRS patients.
EORTC 22951-26001 (Kocher et al. 2011): Randomized,
multi-institution trial of WBRT (n = 81, 30 Gy/10 frac-
tions) vs. observation (n = 79) following either surgery
or SRS for 1–3 brain metastases in patients with stable
systemic disease and ECOG performance status 0–2.
Median time to ECOG performance status deteriora-
tion >2: 10 months with observation and 9.5 months
with WBRT. OS similarly equivalent (~11 months),
although WBRT reduced 2-year relapse at both new
and initial sites. Salvage therapies used more fre-
quently in the observation arm.
University of Cologne (Kocher et al. 2004):
Retrospective review of patients with 1–3 previously
untreated cerebral metastases treated with linac-based
SRS (n = 117, median dose 20 Gy/1 fraction) or WBRT
(n = 138, 30–36 Gy/10 fractions) stratified by RPA
class. Rate of salvage WBRT: SRS group 22 %, WBRT
group 7 %. Significantly longer survival after SRS in
RPA class I (25 vs. 5 months) and class II (6 vs. 4
months) patients; no difference in RPA class III
patients (4 vs. 2.5 months).
SRS for >4 Brain Metastases
University of Pittsburgh (Bhatnagar et al. 2006):

Retrospective review of 105 patients with ≥4 brain
metastases (median 5, range 4–18) treated with single-
session GKRS (median marginal dose 16 Gy/1 fraction)
plus WBRT (46 %), after failure of WBRT (38 %), or
alone (17 %). Median OS 8 months (RPA class I: 18
months, class II: 9 months, and class III: 3 months),
1-year LC 71 %, and median time to progression or new
brain metastases 9 months. Total treatment volume, age,
RPA classification, and median marginal dose (but not
the total number of metastases treated) all significant
prognostic factors on multivariate analysis.
SRS Boost After Resection
Stanford (Soltys et al. 2008): Retrospective review of

76 resection cavities treated with SRS (median mar-
ginal dose 18.6 Gy, mean target volume 9.8 cm3).
Actuarial LC at 6 and 12 months: 88 and 79 %, respec-
tively. Conformality index significantly correlated with
improved LC on univariate analysis; LC 100 % for the
least conformal quartile, and 63 % for all others. Target
volume, dose, and number of fractions not significant.
Recommendation for 2 mm margin around resection
cavities.
Brainstem Lesions
UCSF (Kased et al. 2008): Retrospective review of 42

consecutive patients with 44 brainstem metastases;
median target volume 0.26 cm3, median marginal dose
16 Gy/1 fraction. Brainstem FFP 90 % at 6 months, and
77 % at 1 year. Median survival after SRS 9 months;
significantly longer in those with a single metastases,
non-melanoma histology, and controlled extracranial
disease. Poor outcomes with melanoma and renal cell
histology, as well as target volume ≥1 cm3. Four com-

plications following treatment including ataxia, dis-
equilibrium, facial numbness, and hemiparesis, all of
which were associated with lesion progression as well
as potential radiation effect.
Salvage After SRS
Zindler et al. (2014): Retrospective review of 443

patients with 1–3 brain metastases treated with RS
alone. Salvage treatment for distant brain recurrence
(DBR) in 25 % of patients, 70 % of which had ≤3
lesions. Actuarial DBR rates at 6, 12, and 24 months
after primary SRS were 21, 41, and 54 %, respectively.
Median time to DBR: 5.6 months. DBR-RPA classes:
I = WHO 0 or 1, ≥6 months from RS (OS 10 months);
II = WHO 0 or 1, <6 months from RS (OS 5 months);
III = WHO ≥2 (OS 3 months).
Meningioma
Mayo Clinic (Stafford et al. 2001): Retrospective
review of 190 consecutive patients with 206 meningio-
mas treated by SRS (median marginal dose 16 Gy;
median target volume 8.2 cm3). Prior surgery in 59 %
of patients; 12 % of lesions with atypical or anaplastic
histology; 77 % of tumors involved the skull base. Five-
year CSS for benign, atypical, and anaplastic tumors
was 100, 76, and 0 %, respectively; LC 93, 68, and 0 %,
respectively. Complications attributed to SRS in 13 %
of patients (CN deficits in 8 %, symptomatic parenchy-
mal changes in 3 %, carotid artery stenosis in 1 %, and
cyst formation in 1 %); decrease in functional status
related to radiosurgery in six patients.
University of Pittsburgh (Kondziolka et al. 1999a, b):
Retrospective review of 99 consecutive patients treated
with SRS (43 %) or surgery followed by SRS (57 %).
Median marginal dose 16 Gy; median target volume
4.7 cm3. Five patients previously treated with conven-

tional RT; 89 % of tumors adjacent to the skull base. At
10 years, 11 % LF; PFS worse in patients with prior
resections and multiple meningiomas. New or worsen-
ing neurologic symptoms in 5 % of patients. By survey,
96 % of patients considered treatment a success.
Benign
Germany (Fokas et al. 2014): Retrospective review of

318 patients with histologically confirmed (45 %) or
radiographically presumed (55 %) benign meningi-
oma treated with fractionated stereotactic RT (80 %;
median dose 55.8 Gy/31 fractions), hypofractionated
stereotactic RT (15 %; 40 Gy/10 fractions or 25–35
Gy/5–7 fractions), or SRS (5 %) based on tumor size
and proximity to critical structures. With median fol-
low-up 50 months, 5- and 10-year LC, OS, and CSS
were 93, 89, and 97 %; and 88, 74, and 97 %, respec-
tively. On multivariate analysis, tumor location and age
>66 years were significant predictors of LC and OS,
respectively. Acute worsening of neurologic symptoms
and/or clinically significant acute toxicity after RT in 2
% of patients; no late grade ≥3 toxicity.
University of Pittsburgh (Kondziolka et al. 2014):
Retrospective review of 290 benign meningioma
patients treated with GKRS (median marginal dose 15
Gy, median target volume 5.5 cm3). Prior fractionated
RT in 22 patients, STR in 126 patients, and recurrence
after GTR in 22 patients. Overall tumor control 91 %;
10- and 20-year actuarial PFS from the treated lesion
were both 87 %. Among symptomatic patients, 26 %
improved, 54 % remained stable, and 20 % had a
gradual worsening. No significant difference in control
with prior craniotomy vs. primary GKRS; PFS worse
in those with prior RT and higher-grade lesions.
Santacroce et al. (2012): Retrospective, multicenter
review of 4565 consecutive patients with 5300 benign
meningiomas treated with GKRS (median marginal

dose 14 Gy; median target volume 4.8 cm3). Results of
3768 lesions with >24 months follow-up reported.
Tumor size decreased in 58 % of cases, remained
unchanged in 34 %, and increased in 8 %; overall con-
trol rate 92 %. Five- and 10-year PFS 95 and 89 %,
respectively. Tumor control higher for presumed
meningiomas vs. histologically confirmed grade I
lesions, female vs. male patients, sporadic vs. multiple
meningiomas, and skull base vs. convexity tumors.
Permanent morbidity in 6.6 %.
Prague (Kollová et al. 2007): Retrospective review of
400 benign meningiomas in 368 patients treated with
SRS (median marginal dose 12.5 Gy; median target
volume 4.4 cm3). With median follow-up of 5 years, 70
% of tumors decreased in size, 28 % remained stable,
and 2 % increased in size. Actuarial LC 98 %; worse in
men and with <12 Gy. Temporary toxicity in 10 % and
permanent in 6 %. Peritumoral edema worse with >16
Gy, age >60 years, no prior surgery, preexisting edema,
tumor volume >10 cm3, and anterior fossa location.
Mayo Clinic (Pollock et al. 2003): Retrospective
review of 198 benign meningiomas <3.5 cm3 in mean
diameter treated surgically (n = 136) or with primary
SRS (n = 62; mean marginal dose 18 Gy). No statisti-
cally significant difference in 3- and 7-year PFS for
Simpson Grade I resections (100 and 96 %, respec-
tively) and SRS (100 and 95 %, respectively). SRS
associated with superior PFS relative to Simpson
Grade ≥2 resections, and relative to surgery in gen-
eral, fewer adjuvant treatments (3 % vs. 15 %) and
fewer complications (10 % vs. 22 %).
Atypical and Anaplastic
Northwestern University (Kaur et al. 2014): Systematic

review from 1994 to 2011 analyzing 21 English-
language studies reporting tumor characteristics,
treatment parameters, and clinical outcomes for atypi-

cal and malignant (anaplastic) meningiomas treated
with adjuvant RT or SRS. Median 5-year PFS and OS
for atypical lesions after adjuvant RT were 54 and 68
%, respectively; anaplastic lesions: 48 and 56 %,
respectively. Outcomes data identified for only 23
patients treated with SRS (median marginal dose
18–19 Gy), generally with poor outcomes.
Skull Base
NAGKC (Sheehan et al. 2014): Multi-institutional,

retrospective review of 763 patients with sellar and/or
parasellar meningiomas treated with GKRS (median
marginal dose 13 Gy; median target volume 6.7 cm3);
51 % prior resection, and 4 % prior RT. Median fol-
low-up 67 months. Actuarial PFS at 5 and 10 years 95
and 82 %, respectively; significant predictors of pro-
gression included >1 prior surgery, prior RT, and
tumor marginal dose <13 Gy. Stability or improvement
in neurologic symptoms in 86 % of patients; CN V and
VI improvement in 34 % with preexisting deficits.
Progression of existing neurologic symptoms in 14 %
of patients; new or worsening CN deficits in 10 %
(most likely CN V dysfunction). New or worsening
endocrinopathy in 1.6 % of patients.
NAGKC (Starke et al. 2014): Multi-institution, retro-
spective review of 254 patients with radiographically
presumed (55 %) or histologicially confirmed (45 %)
benign petroclival meningioma treated with GKRS
upfront (n = 140) or following surgery (114). Mean
marginal dose 13.4 Gy; mean target volume 7.5 cm3.
With mean follow-up of 71 months, 9 % of tumors
increased in size, 52 % remained stable, and 39 %
decreased; 94 % of patients had stable or improved
neurologic symptoms. PFS at 5 and 10 years was 93
and 84 %, respectively. Multivariate predictors of
favorable outcome included small tumor volume,
female gender, no prior RT, and lower maximal dose.
Park et al. (2014): Retrospective review of 74 patients

with cerebellopontine angle (CPA) meningioma
treated with GKRS; median marginal of dose 13 Gy,
median target volume 3 cm3. With median follow-up 40
months, 62 % of tumors decreased in size, 35 %
remained stable, and 3 % increased. PFS at 1 and 5
years was 98 and 95 %, respectively. Neurological
improvement in 31 %, stability in 58 %, and worsening
of symptoms in 11 % of patients (most likely trigemi-
nal neuralgia); rate of improvement 1, 3, and 5 years
after GKRS was 16, 31, and 40 %, respectively.
Asymptomatic peritumoral edema in 5 % of patients;
symptomatic adverse radiation effects in 9 %.
Ongoing
EORTC 26021-22021: Phase III, randomized study of

observation vs. conventional RT or SRS for incom-
pletely resected benign meningiomas. Trial closed
3/2006; results pending.
RTOG 0539: Phase II trial of observation for benign
meningiomas status post resection vs. conventionally
fractionated RT or SRS for recurrent benign menin-
gioma, and primary atypical or anaplastic meningioma.
Large margins (1–2 cm) stipulated for fractionated RT
of atypical and anaplastic meningiomas. Trial closed
6/2009; results pending.
Acoustic Neuroma
University of Pittsburgh (Lunsford et al. 2005):

Retrospective review of GKRS outcomes for 829 ves-
tibular schwannoma patients; median marginal dose
13 Gy, mean target volume 2.5 cm3. Ten-year tumor
control rate 97 %; hearing preservation 77 %. Toxicity
notable for <1 % facial neuropathy and <3 % trigemi-
nal symptoms.
University of Pittsburgh (Chopra et al. 2007):

Retrospective review of 216 patients with acoustic
neuroma treated with GKRS; median marginal dose
12–13 Gy, median target volume 1.3 cm3. Median fol-
low-up 5.6 years. Ten-year actuarial resection-free
control rate 98 %; CN V preservation 95 %, and CN
VII preservation 100 %. Preservation of hearing in
patients with >3 years follow-up: 74 % for serviceable
hearing, and 95 % for testable hearing.
Surgery vs. SRS
Marseille, France (Régis et al. 2002): Non-randomized,

prospective series of GKRS (n = 97) vs. microsurgery
(n = 110) for vestibular schwannoma with preoperative
and postoperative questionnaire assessment. Median
follow-up 4 years. GKRS universally superior in terms
of facial motor function (0 % vs. 37 %), CN V distur-
bance (4 % vs. 29 %), hearing preservation (70 % vs.
38 %), overall functionality (91 % vs. 61 %), duration
of hospitalization (3 vs. 23 days), and mean time
missed from work (7 vs. 130 days).
Hypofractionated Stereotactic RT vs. SRS
Amsterdam (Meijer et al. 2003): Prospective trial of

single-fraction (n = 49) vs. fractionated linac-based
SRS (n = 80) for acoustic neuroma; mean tumor diam-
eter ~2.5 cm. Dentate patients treated with 20–25 Gy/5
fractions, and edentate patients treated with 10–12.5
Gy/1 fraction to the 80 % isodose line. Median follow-
up 33 months. Excellent tumor control (100 % vs. 94
%), preservation of hearing (75 % vs. 61 %), preserva-
tion of CN V (92 % vs. 98 %, statistically significant
difference), and preservation of CN VII (93 % vs. 97
%) with both modalities.
Japan (Morimoto et al. 2013): Retrospective review of 26
vestibular schwannomas treated with hypofractionated
robotic radiosurgery to 18–25 Gy/3–5 fractions (median

target volume 2.6 cm3). Progression defined as ≥2 mm
3D post-treatment tumor enlargement. Seven-year PFS
and LC were 78 and 95 %, respectively. Six reports of
late grade ≥3 toxicity. Formal audiometric testing dem-
onstrated 50 % retention of pure tone averages.
Proton Beam Radiosurgery
Harvard (Weber et al. 2003): Eighty-eight consecutive

patients with vestibular schwannoma treated with 3
converging beams aligned to fiducial markers in the
calvarium; maximum dose 13 Gy RBE, median target
volume 1.4 cm3. Actuarial 5-year tumor control 94 %,
and preservation of CN’s V and VII 89 and 91 %,
respectively, but serviceable hearing preservation 33 %.
Proton beam radiosurgery now only used for tumors <2
cm, and in patients without functional hearing.
Paraganglioma
Pollock (2004): Retrospective, single-institution review
of 42 patients with glomus jugulare tumors treated
with single-session GKRS; mean marginal dose of 15
Gy, mean volume 13 cm3. With median follow-up of 3.7
years, 31 % decreased in size, 67 % remained stable,
and 2 % progressed. Seven- and 10-year PFS were 100
and 75 %, respectively. Hearing preservation 81 % at
4 years, with 15 % of patients developing new deficits
including hearing loss, facial numbness, vocal cord
paralysis, and vertigo.
Hypofractionation
Chun et al. (2014): Retrospective, single-institution

review of 31 patients with skull base paragangliomas
treated with robotic radiosurgery to a total dose of
25 Gy/5 fractions. With median follow-up 24 months,

OS and LC were both 100 %; tinnitus improved in 60
% of patients. Overall tumor volume decreased by 37
% (49 % when analyzing subset of patients with ≥24
month follow-up). No grade ≥3 toxicity.
Surgery vs. SRS
Gottfried et al. (2004): Meta-analysis of 7 surgical

series (374 patients) and 8 GKRS series (142 patients)
of glomus jugulare tumors; mean follow-up 4 and 3
years, respectively. LC 92 % with surgery, 97 % with
GKRS. Complications notable for 8 % morbidity from
GKRS, 8 % CSF leak from surgery, and 1.3 % surgical
mortality. Conclusion that both treatments are safe
and efficacious, although inaccessibility of skull base
limits selection of surgical candidates.
Pituitary Adenoma
Sheehan et al. (2005a, b)): Systematic review of 35

peer-reviewed studies involving 1621 patients with
pituitary adenoma treated with SRS. LC >90 %
achieved in most studies, with mean marginal dose
ranging from 15 to 34 Gy/1 fraction. Weighted mean
tumor control rate for all published studies 96 %.
Sixteen cases of damage to the optic apparatus with
doses ranging from 0.7 to 12 Gy. Twenty-one new neu-
ropathies from CN dysfunction, nearly half of which
were transient. Risks of hypopituitarism, RT-induced
neoplasia, and cerebral vasculopathy lower with SRS
than historical rates with fractionated
RT. Heterogeneous quantification of endocrinological
remission for Cushing disease, acromegaly, prolacti-
noma, and Nelson syndrome, with wide variation of
endocrine control. Hormone improvement anywhere
from 3 months to 8 years after SRS, although levels
typically normalize within 2 years.
Hypofractionation
Iwata et al. (2011): Single institution retrospective

review of 100 patients with recurrent/residual non-
functioning pituitary adenomas without a history of
prior RT treated with SRS to 21–25 Gy/3–5 fractions;
median target volume 5.1 cm3. Three-year OS and LC
both 98 %. One case of visual disturbance after treat-
ment, three cases of hypopituitarism in patients not
previously on hormone replacement therapy, and
three cases of transient cyst enlargement.
Hormone Control and Risk of Hypopituitarism
Xu et al. (2013): Retrospective, single institution

review of 262 pituitary adenoma patients treated by
SRS with thorough endocrine assessments immedi-
ately before treatment, and then again at regular fol-
low-up intervals. Tumor control 89 % and remission of
endocrine abnormalities in 72 % of functional ade-
noma patients. Thirty percent rate of new hypopituita-
rism; increased risk with suprasellar extension and
higher marginal dose, but not with tumor volume,
prior surgery, prior RT, or age at SRS.
Vascular Malformations
Arteriovenous Malformation (AVM)
Tokyo, Japan (Maruyama et al. 2005): Retrospective,

single-institution review of 500 AVM patients status
post definitive treatment with GKRS (mean dose 21
Gy; median Spetzler–Martin grade III). Pre-GKRS
rate of spontaneous hemorrhage ~6 %; cumulative
4-year obliteration rate 81 %, 5-year rate 91 %.
Hemorrhage risk reduced by 54 % during the latency
period post-GKRS/pre-obliteration, and 88 % after
obliteration; greatest risk reduction in those who ini-
tially presented with hemorrhage.
University of Maryland (Koltz et al. 2013):

Retrospective review of 102 patients treated with sin-
gle- fraction or staged SRS for AVM’s stratified by
Spetzler–Martin Grade. With mean follow-up of 8.5
years, overall nidus obliteration was 75 % with 19 %
morbidity, both of which correlated with Spetzler–
Martin Grade. For Grade I–V lesions, obliteration
achieved in 100, 89, 86, 54, and 0 % of cases. For AVMs
that were not completely obliterated, the mean reduc-
tion in nidus volume was 69 %.
University of Virginia (Ding et al. 2014): Retrospective
review of 398 Spetzler–Martin Grade III AVMs treated
with SRS (median target volume 2.8 cm3, median pre-
scription 20 Gy). With median 68 months clinical fol-
low-up, complete obliteration in 69 % of lesions after
median of 46 months from SRS. Significant predictors
of response included prior hemorrhage, size <3 cm,
deep venous drainage, and eloquent location. Annual
risk for hemorrhage during the latency period was 1.7
%. Symptomatic radiation-induced complications in
12 % of patients (permanent in 4 %); independent
predictors included absence of pre-SRS rupture and
presence of a single draining vein. Conclusion: SRS for
Spetzler–Martin Grade III lesions is comparable to
surgery in the long-term.
Harvard (Hattangadi-Gluth et al. 2014): Retrospective
review of 248 consecutive patients with 254 cerebral
AVMs treated with single-fraction proton beam ste-
reotactic radiosurgery; median target volume 3.5 cm3,
23 % in eloquent/deep locations, and median prescrip-
tion dose 15 Gy RBE. With median 35 months follow-
up, 65 % obliteration rate, median time to obliteration
31 months; 5- and 10-year cumulative incidence of
total obliteration was 70 and 91 %, respectively.
Univariate and multivariate analyses showed location
and smaller target volume to be independent predic-
tors of total obliteration; smaller volume and higher
prescription dose also significant on univariate
analysis.
Harvard (Barker et al. 2003): Retrospective review of

toxicity data in 1250 AVM patients treated with ste-
reotactic proton beam radiosurgery. Median follow-
up 6.5 years, median dose 10.5 Gy, median target
volume 33.7 cm3 (23 % <10 cm3). Permanent radia-
tion-related deficits in 4 % of patients; median time
to complications 1.1 years. Complication rate related
to dose, volume, deep location, and age; rate <0.5 %
with <12 Gy.
Nagasaki, Japan (Matsuo et al. 2014): Median 15.6-
year results of 51 AVM patients treated with linear
accelerator-based radiosurgery; median prescription
15 Gy, median target volume 4.5 cm3, median Spetzler–
Martin Grade II. Actuarial obliteration rates after 5
and 15 years were 54 and 68 %, which increased to 61
and 90 % when allowing for salvage treatments.
Obliteration rate significantly related to target volume
≥4 cm3, marginal dose ≥12 Gy, and Spetzler–Martin
grade I (vs. others) on univariate analysis (target vol-
ume also significant on multivariate analysis). Post-
treatment hemorrhage observed in 7 cases (14 %),
predominantly within latency period; actuarial post-
treatment bleeding rate ~5 % during the first 2 years,
and 1.1 % upon final observation. Actuarial symptom-
atic radiation injury rates at 5 and 15 years were 12 and
19 %, respectively; target volume ≥4 cm3 and location
(lobular vs. other) were significantly associated with
radiation injury on univariate and multivariate analy-
sis. Cyst formation in five cases (9.8 % of patients;
three asymptomatic, two treated with resection, and
one resolved with steroids).
Staged AVM Treatment
Yamamoto et al. (2012): Thirty-one patients retrospec-

tively identified who underwent intentional 2-stage
GKRS for 32 AVMs with nidus >10 cm3 (mean target
volume 16 cm3, maximum 56 cm3). Low radiation doses

(12–16 Gy) given to the lesion periphery during the
first treatment; second session planned 36 months
after the first. Complete nidus obliteration in 65 % of
patients, and marked shrinkage in the remaining 35 %.
Mild symptomatic GKRS-related complications in 2
patients.
Ding et al. (2013): Eleven patients with large AVMs
(31 ± 19 cm3) divided into 3–7 cm3 sub-targets for
sequential treatment by robotic radiosurgery at 1–4
week intervals. Forward and inverse planning used to
optimize 95 % coverage for delivery of 16–20 Gy;
mean conformality index 0.65.
Cavernous Malformation
Poorthuis et al. (2014): Systematic review and meta-

regression analysis of 63 cohorts involving 3424
patients. Composite outcome of death, nonfatal intra-
cranial hemorrhage, or new/worse persistent focal
neurological deficit was 6.6 per 100 person-years after
surgical excision (n = 2684), and 5.4 after SRS (n = 740;
median dose 16 Gy). However, lesions treated with
SRS significantly smaller than those treated surgically
(14 mm vs. 19 mm).
University of Pittsburgh (Hasegawa et al. 2002a, b):
Retrospective review of 82 consecutive patients
treated with SRS for hemorrhagic cavernous malfor-
mations; annual hemorrhage rate 34 %, excluding the
first hemorrhage. Mean marginal dose 16.2 Gy, mean
volume 1.85 cm3. With mean follow-up of 5 years, aver-
age hemorrhage rate for the first 2 years after radio-
surgery was 12 %, followed by <1 % from years 2
through 12. Eleven patients (13 %) had new neuro-
logical symptoms without hemorrhage after
radiosurgery.
Trigeminal Neuralgia
Primary Treatment
Marseille, France (Régis et al. 2006): Phase I prospec-

tive trial of GKRS (median dose 85 Gy) in 100 patients
with trigeminal neuralgia; 42 % with history of prior
surgery. At 12 months, 83 % pain free, 58 % pain free
and off medication; salvage rate 17 %. Side effects
included mild facial paresthesia in 6 % and hyperes-
thesia in 4 %.
University of Virginia (Sheehan et al. 2005a, b): GKRS
used to treat trigeminal neuralgia in 151 consecutive
patients with median 19 months follow-up. Median
time to pain relief was 24 days; at 3 years, 34 % of
patients were pain free, and 70 % of patients had
improvement in pain. Twelve patients experienced
new onset of facial numbness after treatment, which
correlated with repeat GKRS. Right-sided neuralgia
and prior neurectomy correlated with pain-free out-
comes on univariate analysis; multivariate analysis
similarly significant for right-sided neuralgia.
Brussels, Belgium and Marseilles, France (Massager
et al. 2007): Retrospective stratification of 358 trigemi-
nal neuralgia patients into 3 dosimetric groups: <90 Gy
(no blocking), 90 Gy (no blocking), and 90 Gy with
blocking. Excellent pain control in 66 % vs. 77 % vs. 84
%; good pain control in 81 %, 85 %, and 90 %. Mild
trigeminal toxicity in 15 % vs. 21 % vs. 49 %; bother-
some toxicity in 1.4 % vs. 2.4 % vs. 10 %.
Brisman (2007): Review of 85 patients with trigeminal
neuralgia treated with microvascular decompression
(MVD, n = 24) or GKRS (n = 61) and followed pro-
spectively. Complete pain relief at 12 and 18 months
achieved in 68 % of MVD patients, and 58 and 24 %
of GKRS patients; partial pain relief more equivalent.
No permanent complications.
Retreatment
UCSF (Sanchez-Mejia et al. 2005): Retrospective

review of 32 patients retreated for trigeminal neural-
gia with MVD (n = 19), radiofrequency ablation (RFA,
n = 5), or SRS (n = 8) from an initial cohort of 209
patients. Retreatment rate with RFA (42 %) signifi-
cantly greater than the rate of retreatment with either
MVD (20 %) or SRS (8 %).
Columbia (Brisman 2003): Retrospective review of
335 patients with primary trigeminal neuralgia treated
to a maximum dose of 75 Gy by GKRS, and then 45
re-treated to a maximum dose of 40 Gy GKRS (mean
interval 18 months). Final pain relief was 50 % or
greater in 62 % of patients; absence of prior surgery
was an independent predictor of response to retreat-
ment. Significant dysesthesias in 2 patients; no other
serious complications.
Zhang et al. (2005): Retrospective study of 40 trigemi-
nal neuralgia patients initially treated with 75 Gy GKRS,
and then retreated with 40 Gy GKRS. Landmark-based
registration algorithm used to determine spatial rela-
tionship between primary and retreatment isocenters.
Trend toward better pain relief with farther distance
between isocenters; however, neither placing the second
isocenter proximal or distal to the brainstem was signifi-
cant. Mean distance 2.9 mm in complete or nearly com-
plete responders vs. 1.9 mm in all others.
Dvorak et al. (2009): Retrospective study of 28 tri-
geminal neuralgia patients initially treated to median
80 Gy GKRS, then retreated to median 45 Gy GKRS
after a median 18 month interval. Univariate analysis
showed no significant predictors of pain control or
complication. However, when combining peer-
reviewed retreatment series (215 total patients), both
improved pain control and new trigeminal dysfunction
were associated with greater dose: cumulative dose
>130 Gy likely to result in >50 % pain control as well
as >20 % risk of new dysfunction.
Pineal Tumors
University of Pittsburgh (Hasegawa et al. 2002a, b):

Retrospective review of 16 patients treated with SRS
for pineal parenchymal tumors (10 pineocytomas, 2
mixed pineocytoma/pineoblastoma, and 4 pineoblas-
toma). Mean dose 15 Gy, mean target volume 5 cm3.
Actuarial 2 and 5 year OS 75 and 67 %, respectively;
CR 29 %, PR 57 %, SD 14 %. LC 100 % although 4
patients died from leptomeningeal or extracranial
spread. Two cases of gaze palsy 7 and 13 months after
SRS attributed to treatment, one resolved with ste-
roids and the other persisted until death.
Marseille, France (Reyns et al. 2006): Retrospective
review of 13 patients with pineal parenchymal tumors
(8 pineocytomas and 5 pineoblastomas) treated with
SRS (mean marginal dose 15 Gy). With mean follow-
up 34 months, LC 100 %; 2 pineoblastomas progressed
outside of SRS field resulting in death. No major mor-
tality or morbidity related to SRS.
England (Yianni et al. 2012): Retrospective review of
44 patients with pineal tumors treated with SRS (11
pineal parenchymal tumors, 6 astrocytomas, 3 ependy-
momas, 2 papillary epithelial tumors, and 2 germ cell
tumors). Mean dose 18.2 Gy, mean target volume
3.8 cm3. One- and 5-year PFS 93 and 77 %, respec-
tively, but separating aggressive tumors from indolent
lesions showed 5-year PFS 47 and 91 %, respectively.
Tumor grade, prior RT, and radionecrosis associated
with worse outcome.
Functional Disorders
Epilepsy
UCSF (Chang et al. 2010): Prospective, randomized

trial involving 30 patients with intractable medial tem-
poral lobe epilepsy treated with 20 Gy/1 fraction vs. 24
Gy/1 by GKRS to the amygdala, 2 cm of the anterior

hippocampus, and parahippocampal gyrus.
Nonsignificant difference in seizure control between
arms (59 % vs. 77 %), although early MRI alterations
predictive of long-term seizure remission.
Parkinson Disease and Essential Tremor
Japan (Ohye et al. 2012): Prospective, multicenter

study of 72 patients with intractable Parkinson disease
or essential tremor treated with selective thalamotomy
by GKRS with a single 130 Gy shot to the lateral part
of the ventralis intermedius nucleus (located 45 % of
the thalamic length from the anterior tip). Excellent or
good response with improved tremor in 43 of 53
patients (81 %) who completed 24 months of follow-
up. No permanent clinical complications.
University of Pittsburgh (Kondziolka et al. 2008):
Retrospective review of GKRS thalamotomy in 31
patients with medically refractory essential tremor.
Nucleus ventralis intermedius treated with 130–140 Gy
in a single fraction. With median follow-up of 26 months,
mean tremor score improved by 54 %, and mean hand-
writing score improved by 39 %, with the majority of
patients (69 %) seeing improvement in both. Permanent
mild right hemiparesis and speech impairment in 1
patient 6 months after radiosurgery; 1 patient with tran-
sient right hemiparesis and dysphagia.
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Chapter 5
Spine
David R. Raleigh, Igor J. Barani, and David A. Larson
Pearls
The spinal cord begins at the foramen magnum and, in
adults, typically ends at the level of L1–L2. Below the
termination of the cord, the spinal subarachnoid space
extends to S2–S3, and the spinal canal continues infe-
riorly into the coccyx.
Metastases to the vertebrae and epidural space com-
pose the vast majority of tumors adjacent to the spinal
cord (Linstadt and Nakamura 2010).
Primary spinal cord tumors, such as chordoma and chon-
drosarcoma, account for 4–6 % of all CNS neoplasms
and are slightly more common in pediatric patients.
Primary tumors involving the spinal cord typically
originate within the spinal canal (65 %), but may also
D.R. Raleigh
I.J. Barani () • D.A. Larson
Surgery, University of California, San Francisco,
1600 Divisadero Street, Basement Level, San Francisco, CA
94143-1708, USA
e-mail: Igor.Barani@ucsf.edu

arise from the spinal cord (10 %), or vertebral bodies

(10 %).
Presentation ranges from incidental discovery on
surveillance imaging (especially in patients on high-
dose steroids) to full paralysis, but the most common
complaint is pain.
Brown-Sécquard syndrome: Ipsilateral motor and fine
touch impairment, and contralateral loss of pain and
temperature sensation.
Crude local control (LC) after spine SBRT for spine
metastases ranges from 80 to 100 % (Lo et al. 2010);
LC with conventional radiotherapy is approximately
86 % for non-mass-type metastases, but falls to 46 %
for bulky lesions (Mizumoto et al. 2011).
The risk–benefit ratio for SBRT treatment of
meningioma, schwannoma, and malignant tumors of
the spinal cord (glioblastoma, ependymoma, and
metastases) relative to standard fractionation is not
known.
SBRT should be performed before cement kypho-
plasty to prevent extravasation of active tumor into
the epidural space (Cruz et al. 2014).
ASTRO guidelines Life expectancy ≥3 months

for general spine Limited disease burden
SBRT (2011) Previously radiated location(s)
Postoperative radiation
Favor enrollment on a clinical trial
Spinal cord Limited compression (1–2 segments)
compression Sub-acute presentation (outcome
unlikely to be impacted by protracted
SBRT planning)
Re-irradiation
Primary spinal cord Postoperative adjuvant setting
neoplasms Salvage
5. Spine 81
Workup
H&P with emphasis on neurologic components.
Review of systems, including:
Focal weakness.
Focal sensory changes.
Bowel or bladder incontinence, and perianal numb-
ness which could indicate cauda equina involvement.
Back pain.
Laboratories not typically required, except in cases
where adjacent viscera may be invaded or if there is
concern for hematologic malignancy (then CBC, CMP,
LFTs, etc.).
Imaging.
MRI spine with gadolinium remains the gold stan-
dard for assessment of spinal cord neoplasms, and is
also critical for SBRT targeting.
CT myelogram (standard or metrizamide-
enhanced) is often useful in patients with metallic
vertebral implants or a permanent pacemaker. At
some institutions, CT myelograms are standard
practice for spine SBRT planning.
MRI neurogram may be used to assess for nerve
root involvement but has limited utility in SBRT
planning.
Simulation and Treatment Planning
Invasive stereotactic frames that attach to spinous

processes (Hamilton and Lulu 1995; Hamilton et al.
1995) have fallen out of favor with the advent of
noninvasive immobilization devices that allow for tar-
geting accuracy within 1–2 mm and 1–2° (Ryu et al.
2003; Yenice et al. 2003).
Fluoroscopic placement of percutaneous gold fiducial

markers into vertebral pedicles can be used to enhance
intrafraction tumor targeting and tracking, but spinal
tracking is most often sufficient.
Insertion of a percutaneous balloon into pre-sacral
space may be considered to displace the rectum if
needed for definitive treatment of complex sacral
lesions.
CT simulation with slice thickness ≤3 mm (1–1.5 mm
recommended).
MRI and/or CT myelogram should be used in patients
with vertebral hardware.
Co-registration with MRI or PET/CT images when
available.
Target volumes:
GTV: Residual disease on CT/MRI.
CTV: GTV plus postoperative bed at high risk for
recurrence.
PTV: CTV + 1.5–2 mm margin excluding critical
neural structures.
Dose Prescription
No randomized studies are available to provide firm

recommendations for dose selection, and a clear dose-
response relationship for pain control has not been
established. However, there is a trend for symptomatic
improvement (Ryu et al. 2003, 2007; Gerszten et al.
2006) and improved control of radioresistant histo-
logic subtypes with increased dose (Gerszten et al.
2005a, b; Yamada et al. 2008).
Limited disease in patients without prior radiation:
16–24 Gy in 1 fraction.
Multi-segment disease without prior radiation:
20–27 Gy in 2–3 fractions.
Multi-segment disease in previously irradiated field:
20–25 Gy in 5 fractions.
Chordoma: 40 Gy in 5 fractions (UCSF experience).
5. Spine 83
Dose Delivery
For multifraction regimens, doses are delivered every

other day or twice weekly.
Initial verification by kV X-ray or CBCT, aligned to
spine or surrogate fiducial markers of position.
Interval verification during treatment delivery with
repeat kV X-ray films or CBCT for longer treatments
or patients unable to remain immobile (Figs. 5.1, 5.2,
and 5.3).

Acute toxicities (≤6 weeks):
Low risk of acute, self-limited esophagitis, nausea/
vomiting, and loose stool with treatment of cervico-
thoracic, lumbar, and sacral spinal lesions, respec-
tively; manage with antiemetic and antidiarrheal
agents.
Cutaneous toxicities are rare, mild, and generally
limited to treatment of lesions extending into the
posterior paraspinous space.
Late toxicities (>6 weeks):
Vertebral body compression fracture is a fairly low-
risk adverse event after conventional radiotherapy
(~5 %), but estimates range from 11 to 39 % after
spine SBRT (vide infra).
Serious late effects to the esophagus and bronchi,
such as necrosis and ulceration, are rare but may
require surgical intervention.
Late toxicity to the brachial plexus, lumbar plexus
and spinal cord, including both self-limited myelop-
athy and chronic progressive myelopathy, are simi-
larly uncommon and may be mitigated with
hyperbaric oxygen treatment.
Fig. 5.1. SBRT for vertebral body metastasis. (a–c) Thirty-nine year-
old male with stage IVC nasopharyngeal carcinoma and a painful
L1 vertebral body metastasis extending to the bilateral epidural
space and right psoas muscle. The metastasis was treated with rapid
arc stereotactic radiosurgery to a total dose of 2400 cGy in a single
fraction with 6 MV photons prescribed to the 87 % isodose line
Fig. 5.2. Postoperative SBRT for primary spine tumor. (a–c) Forty-
nine year-old male with a remote history of medullary thyroid cancer
who subsequently developed a painful left posterior 7th rib lesion that
was treated with a course of palliative radiotherapy to 3300 cGy in 11
fractions at an outside institution. The lesion continued to grow over
the following 2 years, and a biopsy demonstrated chondrosarcoma.
Following gross total resection and two subsequent recurrences, the
GTV was treated with rapid arc stereotactic radiosurgery to a total
dose of 3500 cGy in 5 fractions, with 2000 cGy to the postoperative
bed, using 6 MV photons prescribed to the 88 % isodose line
Fig. 5.3. Clival chordoma SBRT. Thirty year-old female with a clival
chordoma status post gross total endoscopic endonasal transsphe-
noidal resection, followed by repeat gross total resection for a recur-
rence 1 year later. The tumor was treated with adjuvant robotic
radiosurgery to a total dose of 4000 cGy in five daily sequential
fractions with 6 MV photons prescribed to the 83 % isodose line.
Beam angles are shown at the top left, and proceeding clockwise are
axial, coronal, and sagittal CT images with isodose lines and the
PTV in red color wash
Lhermitte’s syndrome, an electric sensation running

down the back into the limbs, often precedes frank
neurologic deficits of radiation myelopathy.
H&P and MRI spine every 2–3 months or as clinically
indicated for the first 2-years, followed by imaging
every 6 months for the next 3 years, and yearly imaging
thereafter.
5. Spine 87
Evidence
Dose and Technique
Yamada et al. (2005): Noninvasive immobilization for

paraspinal stereotactic or image-guided radiotherapy
with setup accuracy within 2 mm. Thirty-five patients
(14 primary tumors and 21 metastases) with gross
disease involving the spinal canal who were either
previously irradiated or treated with doses beyond
conventional spinal cord tolerance. PTV = gross dis-
ease with a 1 cm margin, excluding the spinal cord.
For primary treatments, median PTV dose 7000 cGy
in 33 fractions with V100 of 90 %; median cord Dmax
68 %. In re-irradiation cases, median PTV dose 20 Gy
in 5 fractions with V100 of 88 %; median cord Dmax
34 %. Median follow-up 11 months; no radiation
myelopathy. Palliation from pain, weakness, or pare-
sis in 90 % of patients with >3 months of follow-up.
LC 75 and 81 % for secondary and primary malignan-
cies, respectively.
Chang et al. (2007): Prospective phase I/II study of
SBRT for spinal metastases in 63 patients with 74
tumors treated at MDACC (30 Gy in 5 fractions or
27 Gy in 3 fractions; spinal cord Dmax ≤10 Gy). In
previously radiated patients (n = 35, 56 %), prior dose
≤45 Gy. Median follow-up 21.3 months; no neuropathy
or myelopathy. Actuarial 1-year PFS 84 %. Primary
mechanisms of failure limited to recurrence in adja-
cent bones (i.e., pedicles and posterior vertebral ele-
ments), and epidural space. Narcotic usage declined
from 60 to 36 % at 6 months.
Ryu et al. (2008): Forty-nine patients with 61 separate
spinal metastases treated with single-session SBRT
from 10 to 16 Gy. Spinal cord limited to ≤10 Gy for
≤10 % of the cord volume 6 mm superior and inferior
to the treated segment. Median time to pain relief 14
days (earliest within 24 h). Complete pain relief in
46 % and partial relief in 19 %. Overall pain control

rate for 1 year was 84 %; median duration of relief 13.3
months. Trend toward increasing pain relief with
≥14 Gy. No clinically detectable late toxicity.
Yamada et al. (2008): One-hundred three consecutive
spinal metastases in 93 patients treated with 18–24 Gy
in 1 fraction (median 24 Gy) prescribed to the 100 %
isodose line; spinal cord Dmax ≤14 Gy. Patients with
high-grade cord compression, mechanical instability,
and prior history of RT excluded. Median follow-up
and OS both 15 months; actuarial LC 90 % with
median time to LF 9 months. Radiation dose, but not
histologic subtype, was a significant predictor of
LC. Acute toxicity limited to grade ≤2 events; no late
toxicity. All patients without local failure reported
durable palliation of symptoms.
Amdur et al. (2009): Prospective phase II study of
SBRT for spinal cord metastases involving 25 sites in
21 patients treated with 15 Gy in 1fraction. Primary
endpoint was toxicity; spinal cord Dmax ≤12 Gy in
patients with no prior radiotherapy (n = 9), and ≤5 Gy
for salvage cases (n = 12). With median follow-up 11
months, 95 % LC and 43 % pain improvement, but
1-year OS 25 % and PFS 5 %. Acute toxicity limited to
grade ≤2 dysphagia or nausea; no late toxicity.
Spinal Cord Compression and Retreatment
Milker-Zabel et al. (2003): Eighteen patients with 19

previously irradiated spinal cord metastases (median
dose 38 Gy) re-treated due to progressive pain (n = 16)
or neurologic symptoms (n = 12). Median time to re-
treatment 17.7 months. Five patients treated with frac-
tionated conformal radiotherapy (FCRT), 14 treated
with IMRT; all immobilized for extracranial stereo-
taxy. Median re-treatment dose 39.6 Gy in 2 Gy frac-
tions. After median of 12 months of follow-up, OS
65 %, LC 95 %, pain relief 81 %, and neurologic
5. Spine 89
improvement 42 %. Tumor size unchanged in 84 % of

cases. No clinical late toxicity.
Gerszten et al. (2007): Single institution cohort of
393 patients with spinal cord compression treated
with 12.5–25 Gy robot-assisted SBRT in 1 fraction
(mean 20 Gy) and followed prospectively. Five hun-
dred metastases, 67 % previously treated with
EBRT. Long-term improvement in pain for 86 % of
patients; 84 % (30 of 35) with progressive neuro-
logical deficit experienced clinical improvement.
LC was 90 and 88 % for primary and salvage SBRT,
respectively. No reports of radiation myelopathy.
Sahgal et al. (2009): Single institution retrospective
review of 39 consecutive patients with 60 paraspinal
metastases treated with robot-assisted SBRT. Median
dose 24 Gy in 3 fractions prescribed to the 60–67 %
isodose line. Sixty-two percent of lesions previously
treated with EBRT. Median OS 21 months; 1- and
2-year PFP was 85 and 69 %, respectively. For re-irra-
diation cases, 1-year PFP was 96 %. No significant dif-
ferences in OS or PFP between salvage and de novo
treatments. No reports of radiation-induced myelopa-
thy or radiculopathy in the 39 cases with ≥6 months
follow-up. All patients with local failure experienced
worsening of pain; all others stable at best, but no stan-
dardized pain quantification used.
Chordoma and Other Primary Tumors

of the Spine and Skull Base
Martin et al. (2007): Twenty-eight patients with chor-
doma (n = 18) or chondrosarcoma (n = 10) of the skull
base treated with Gamma Knife SRS as either primary
(n = 2) or adjuvant treatment. Twenty-two patients pre-
viously received fractionated radiotherapy prior to
radiosurgery (mean dose 65 Gy and 75 CGE). Mean
tumor volume at SRS 9.8 cm3. Median dose to the
tumor margin 16 Gy in 1 fraction (range 10.5–25 Gy)
prescribed to the 50 % isodose line in all but 1 patient.

Transient acute toxicity in 1 patient. Median follow-up
7.7 years. Five-year actuarial LC for chondrosarcoma
80 ± 10 %; chordoma actuarial LC and survival
63 ± 10 % at both 5- and 10-years. No significant fac-
tors identified for tumor control.
Henderson et al. (2009): Eighteen chordoma patients
treated with stereotactic robotic radiosurgery; 44 %
mobile spine, 39 % clivus, and 17 % sacral tumors.
Median tumor volume 128 cm3 treated with a median
dose of 35 Gy in 5 fractions; salvage cases treated with
28 Gy in 4 fractions. Five-year LC 59 %, OS 74 %, and
DSS 89 %. No improvement in pain or quality of life.
Recommendation for 40 Gy in 5 fractions to gross
tumor and at least a 1 cm margin based on modeling
with α/β of 2.45 for chordoma.
North American Gamma Knife Consortium (Kano
et al. 2011): Seventy-one patients status post SRS for
chordoma from six institutions. Median target volume
7.1 cm3, and median marginal dose 15 Gy. Five-year
actuarial OS 80 %; 93 % for patients with no prior
fractionated RT (n = 50), and 43 % for prior RT group
(n = 21). Younger age, longer interval between initial
diagnosis and SRS, no prior RT, <2 cranial nerve defi-
cits, and smaller tumor volume were significantly
associated with longer survival. Five-year overall LC
66 %; 69 % for no prior RT, and 62 % for prior
RT. Older age, prior RT, and large tumor volume all
significantly associated with worse tumor control.
Thirty percent of patients with pretreatment neuro-
logic deficits experienced improvement; median time
to response 4.6 months.
Jiang et al. (2012): Twenty patients with chordoma
treated with stereotactic robotic radiosurgery (11 pri-
mary adjuvant therapy, 9 salvage); 65 % clival lesions.
Average tumor volume 16 cm3; mean marginal dose of
32.5 Gy in 1–5 fractions to the 79 % isodose line.
With median follow-up 34 months, LC 55 %; 82 % in
5. Spine 91
primary adjuvant cases, and 29 % in salvage cases.

Five-year OS 52.5 %. Status of symptoms not reported.
Yamada et al. (2013): Twenty-four patients with chor-
doma of the sacrum (n = 10) and mobile spine (n = 14)
treated with single-fraction SRS (median dose 24 Gy,
with median V100 95 %). Treatment given in both the
adjuvant (n = 7) and neoadjuvant setting (n = 13),
although only six patients proceeded to surgery.
Seven patients treated for postoperative recurrence.
With median follow-up 24 months, LC 95 %; 1 case of
progression 11 months after SRS. Toxicity limited to 1
case sciatic neuropathy and 1 case vocal cord paralysis.
Status of symptoms not reported.
Vertebral Body Compression Fracture (VCF)
Rose et al. (2009): 62 patients with 71 spinal metasta-

ses treated with single-fraction SBRT (median 24 Gy);
predominance of lytic spinal lesions (65 %). With
median follow-up of 13 months, VCF occurred in 27
(39 %) treated sites after a median time of 25 months.
HR for VCF: osteolytic tumors 3.8; >40 % vertebral
body involvement 3.9; and lesions located from T10
through the sacrum 4.6.
Sahgal et al. (2013): Pooled retrospective study of 252
patients with 410 spinal segments treated with SBRT
at MDACC, Cleveland Clinic, and University of
Toronto. Median follow-up and OS of 11.5 and 16
months, respectively. Twenty-seven new VCFs and 30
cases of VCF progression (overall incidence 14 %).
Median time to VCF 2.46 months, with 65 % of events
occurring in the first 4 months. Dose per fraction iden-
tified as a significant predictor of VCF on univariate
and multivariate analysis; baseline VCF, lytic tumors,
and spinal deformity all significant on multivariate
analysis. Relative to ≤19 Gy per fraction, the HR for
VCF with ≥24 Gy and 20–23 Gy per fraction was 5.25
and 4.91, respectively.
Late Toxicity
Ryu et al. (2007): Retrospective analysis of 230 lesions

treated with single-fraction SBRT to the gross tumor
plus vertebral body and pedicles, and/or posterior ele-
ments in 177 patients without a history of prior radio-
therapy to the spine. Prescription ranged from 8 to
18 Gy to the 90 % isodose line; no PTV margin; spinal
cord volume defined as 6 mm superior and inferior to
the target. Among the patients treated with 18 Gy, the
average dose to the 10 % spinal cord volume was
9.8 ± 1.5 Gy. Median follow-up 6.4 months; 1-year sur-
vival 49 %. One case of radiation myelopathy among
the 86 patients alive >1 year after treatment.
Gomez et al. (2009): Retrospective analysis of 119
paraspinal thoracic sites treated with single-fraction
SBRT (median dose 24 Gy) in 114 patients. Median
Dmax to esophagi and bronchi were 12.5 Gy and
11 Gy, respectively. At a median follow-up of 11.6
months, seven episodes of grade ≥2 esophageal toxic-
ity (one of which required gastric pull-up for fistula
formation), and two cases of grade ≥2 bronchial toxic-
ity; no cases of pneumonitis.
Sahgal et al. (2010): Dosimetric report of
radiation-induced myelopathy in five patients after
primary SBRT for spinal tumors. Radiation myelopa-
thy observed with Dmax of 10.6–14.8 Gy in 1 fraction,
25.6 Gy in 2 fractions, and 30.9 Gy in 3 fractions to the
thecal sac. When compared to dosimetric data from 19
patients without spinal cord myelopathy after SBRT,
there was a significant interaction between patient
subsets based on normalized BED. Modeling with α/β
value of 2 for spinal cord late effect and 10 for tumor
effect suggests that 10 Gy in 1 fraction and up to
35 Gy2 in 5 fractions carries a low risk of radiation-
induced myelopathy.
Sahgal et al. (2012): Dosimetric report of radiation-
induced myelopathy after salvage SBRT in five
5. Spine 93
patients who initially received conventional EBRT to

the spine (median 40 Gy in 20 fractions). When com-
pared to a group of 14 salvage patients without radia-
tion myelopathy, the mean EQD2 maximum point
dose (Pmax) to the thecal sac was significantly higher in
those with radiation myelopathy (67.4 Gy vs. 20 Gy),
as was the total Pmax (105.8 Gy vs. 62.3 Gy). Modeling
suggests that SBRT given at least 5 months after con-
ventional palliative radiotherapy with a re-irradiation
thecal sac Pmax EQD2 of 20–25 Gy appears to be safe
provided the total Pmax EQD2 does not exceed 70 Gy,
and the thecal sac Pmax EQD2 comprises no more than
one-half of the total EQD2.
Ongoing
RTOG 0631: Randomized, prospective, multicenter

trial of single fraction spine SBRT to 8 Gy vs. 16–18 Gy
(1:2 randomization), based on the equivalent results of
30 Gy in 10 fractions vs. 8 Gy in 1 fraction AP/PA from
RTOG 97–14 (Hartsell et al. 2005). Patients stratified
by number of spine metastases, tumor histology, and
intended SBRT dose. Primary endpoint was pain con-
trol; target enrollment 380 patients.
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et al. Phase I/II study of stereotactic body radiotherapy for spinal
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2007;7(2):151–60.
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sation following a cement augmentation procedure for vertebral
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Gerszten PC, Burton SA, Ozhasoglu C, Welch WC. Radiosurgery for
spinal metastases: clinical experience in 500 cases from a single
institution. Spine (Phila Pa 1976). 2007;32(2):193–9.
Gerszten PC, Burton SA, Quinn AE, Agarwala SS, Kirkwood
JM. Radiosurgery for the treatment of spinal melanoma metasta-
ses. Stereotact Funct Neurosurg. 2005b;83(5-6):213–21.
Gomez DR, Hunt MA, Jackson A, O’Meara WP, Bukanova EN,
Zelefsky MJ, et al. Low rate of thoracic toxicity in palliative para-
spinal single-fraction stereotactic body radiation therapy.
Radiother Oncol. 2009;93(3):414–8.
Hamilton AJ, Lulu BA. A prototype device for linear accelerator-
based extracranial radiosurgery. Acta Neurochir Suppl. 1995;63:
40–3.
Hamilton AJ, Lulu BA, Fosmire H, Stea B, Cassady JR. Preliminary
clinical experience with linear accelerator-based spinal stereotac-
tic radiosurgery. Neurosurgery. 1995;36(2):311–9.
Hartsell WF, Scott CB, Bruner DW, Scarantino CW, Ivker RA, Roach
3rd M, et al. Randomized trial of short- versus long-course radio-
therapy for palliation of painful bone metastases. J Natl Cancer
Inst. 2005;97(11):798–804.
Henderson FC, McCool K, Seigle J, Jean W, Harter W, Gagnon GJ.
Treatment of chordomas with CyberKnife: georgetown university
experience and treatment recommendations. Neurosurgery.
2009;64(2 Suppl):A44–53.
Jiang B, Veeravagu A, Lee M, Harsh GR, Lieberson RE, Bhatti I,
et al. Management of intracranial and extracranial chordomas
with CyberKnife stereotactic radiosurgery. J Clin Neurosci.
2012;19(8):1101–6.
Kano H, Iqbal FO, Sheehan J, Mathieu D, Seymour ZA, Niranjan A,
et al. Stereotactic radiosurgery for chordoma: a report from the
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Milker-Zabel S, Zabel A, Thilmann C, Schlegel W, Wannenmacher
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Oncol Biol Phys. 2003;55(3):583–93.
Chapter 6
Head and Neck
Sue S. Yom
Pearls
~52,140 cases/year and 11,460 deaths in the USA from
head and neck cancer (M:W, ~3:1), comprising 6.5 % of
new cancer diagnoses in the USA (Jemal et al. 2010).
5-year survival rates range between 50 and 75 % but
for local-regionally advanced disease (60 % of new
diagnoses), they are as low as 30 % (Ries et al. 1988;
Vokes et al. 1993).
5-year survival for early local recurrence ~25–35 %
and for more advanced recurrence, ~15–20 % (Lee &
Esclamado 2005).
At present SBRT has no clearly established or widely
accepted role in the definitive management of newly
diagnosed, non-metastatic disease or for curative
intent multimodality reirradiation.
The potentially serious risks of SBRT should be cau-
tiously weighed against the competing risks of symp-
tomatic tumor progression and the feasibility and
efficacy of alternative treatment options.
S.S. Yom ()

San Francisco, 1600 Divisadero Street, Suite H-1031,
e-mail: yoms@radonc.ucsf.edu

98 S.S. Yom
Work-Up
H&P, including performance status, HPV status, smok-
ing and alcohol history, prior history of treatment to
the head and neck.
Review of symptoms, including
Bleeding.
Pain.
Weight loss/nutritional status.
Pre-existing dysphagia.
Neuropathies.
Laboratories
CBC, BUN, Cr, LFTs, alkaline phosphatase, and
LDH.
Imaging
MRI of the primary site and neck ± upper
mediastinum.
CT chest with contrast ± CT abdomen and pelvis or
PETCT as indicated.
Pathology
FNA or ultrasound/CT-guided biopsy for accessible
lesions.
Early-stage head and neck cancers are definitively
managed by local therapy, with single-modality surgi-
cal resection or external beam radiation therapy
(EBRT) as usual standard of care. EBRT is more fre-
quently employed for medically inoperable, high-risk,
or elderly patients.
Multimodal therapy, nearly always including EBRT
combined with surgery, chemotherapy, or both, is fre-
quently employed for locally or regionally advanced
head and neck cancer.
SBRT is now selectively employed at a limited number
of centers for small-volume recurrence or palliation.
6. Head and Neck 99
SBRT has been reported as a fractionated stereotactic

boost following definitive (chemo)radiation for locally
advanced nasopharyngeal cancers.
A few reports exist combining SBRT with concurrent
targeted therapy or cytotoxic chemotherapy but these
combinations remain investigational.
Thin-cut CT (1–1.5 mm) thickness recommended.

GTV contoured from fusion of MRI with/without
gadolinium contrast, merged in the area of interest to
the planning CT.
CTV margins may range from 0 to 10 mm depending
on clinical scenario:
For recurrent disease, margins up to 5–10 mm may
be considered depending on the degree of tumor
infiltration into surrounding tissues.
For well-delineated disease at the skull base, where
high-stability or real-time localization of the setup
is expected, 0–3 mm margins could be considered.
For palliation, no margin may be prudent to mini-
mize toxicity.
PTV = CTV + 1–5 mm (dependent upon available
center-specific image guidance and site-specific motion
considerations).
State of the art tracking localization or frequent IGRT
are recommended to reduce setup uncertainty and
margins.
Goal should be for low-dose to proximal OARs,
achieved by use of an increased number of beams and
angles, as well as minimization of margins.
Phantom-based QA on all treatment plans prior to
delivery.
100 S.S. Yom
Dose Prescription
Dose and fractionation outside of the range of conven-

tional fractionation for head and neck cancer (1.8–2.0
Gy/fraction/day) are not clearly defined in terms of
alterations in safety profile or gains in efficacy.
Planning should be determined with a high level of
attention to potential adjacent normal tissue toxicity.
For SBRT-based single-modality reirradiation and
SBRT boost following EBRT, prescriptions vary
widely depending on the clinical scenario; practitio-
ners are advised to consult the primary literature to
identify applicable solutions. For reirradiation, the
most commonly reported dose range is 30–50 Gy over
5 fractions.
Ideally prescribe to ≥80 % isodose line (IDL), ≥95 %
PTV coverage with prescription dose; depending on
characteristics of treatment planning system, 50–60 %
IDL is acceptable only if high-dose heterogeneity and
fall off are thoroughly reviewed for safety.
Composite planning should be employed in cases of
reirradiation, with appropriate BED conversion for
dose summation.
Dose Limitations
Dose and fractionation schemas largely empirically

determined.
Almost no reports address normal organ tolerances
for hypofractionated regimens in any detail.
A dose-escalation study of SBRT-based reirradiation
at the University of Pittsburgh used the following gen-
eral constraints for a 5-fraction regimen: spinal cord ≤ 8
Gy, brain stem ≤ 8 Gy, larynx ≤ 20 Gy, and mandi-
ble ≤ 20 Gy. Doses given to the oral cavity and parotid
glands were based on patient-specific factors.
6. Head and Neck 101
A prospective phase II French study restricted the

repeat dose to a fully previously radiated spinal cord
to ≤ 6 Gy point dose over 6 fractions.
In general, the dose per fraction should be less than
2.5 Gy per fraction to as much tissue as possible, with
special attention to pharyngeal, vascular, or other reir-
radiated structures prone to late complications. Tissue
receiving above 4 Gy per fraction should be strictly
minimized.
Dose Delivery
Dose often delivered in fractions given every other

day; consecutive daily treatments should warrant addi-
tional caution.
Setup may be isocentric or non-isocentric depending
upon SBRT delivery system.
Verification by kV XR or CBCT, aligned to visualized
tumor or surrogate markers of position.
Flexion of the cervical neck can result in interfrac-
tional variability of setup of a few millimeters.
Intrafractional tumor motion may be as much as sev-
eral millimeters in areas affected by jaw opening or
laryngeal/swallowing motions.

Common acute toxicities (<6 weeks):
Fatigue: Generally early-onset and self-limiting.
Dermatitis: Entrance and exit doses can be reduced
with increased numbers of beams to minimize
radiation dermatitis. Mild-to-moderate: skin reac-
tion treated with supportive care, including topical
moisturizers, analgesics, low-dose steroids, and anti-
microbial salves.
102 S.S. Yom
Mucositis: Critical to minimize target volumes to

reduce pain and dysphagia related to this toxicity.
Treated with topical preparations including
lidocaine-based solutions and pain medications.
Nutritional status should be carefully monitored.
Severe late toxicities (>6 weeks)
Brachial plexopathy: May present with neuropathic
pain or with motor/sensory changes in the upper
extremities. MRI of brachial plexus and upper spine
may be diagnostic and rule out tumor recurrence.
Limited treatment options include supportive care
and occupational therapy.
Skin or soft tissue necrosis: For persistent non-
healing lesions, consider hyperbaric oxygen therapy
and tocopherol pharmacotherapy.
Esophageal stricture or fistula: Can occur after
treatment of hypopharyngeal or cervical esopha-
geal inlet. More possible in the reirradiation setting.
Treatment options include dilation or stent
placement.
Vasculopathy: Vascular erosion may lead to limited
hemoptysis or massive hemorrhage and death
(especially seen in reirradiation setting).
Osteoradionecrosis: May occur in the jaw, skull
base, or spine. Worsened by infectious complica-
tions and in proximity to vascular structures, may
raise the risk of hemorrhage.
Brain necrosis: Highest risk within areas of high
cumulative dose. May require neurosurgical inter-
vention and potentially fatal.
CT or PETCT every 3–4 months × 3 years, every 6
months × 2 years, every 12 months thereafter for rou-
tine follow-up.
Neurologic/vascular status should be carefully fol-

lowed; symptoms of headache, dizziness, or TIA should
be investigated immediately.
Infectious complications of the soft tissue or bone
must be vigorously addressed due to high potential for
osteoradionecrosis, soft tissue necrosis, and/or vascular
exposure and blowout.
Evidence
Boost/Recurrence for Nasopharyngeal Carcinoma
Stanford University reported mature results for 82

patients given a median EBRT dose of 66 Gy followed
by single-fraction 7–15 Gy SBRT boost. Most had con-
current cisplatin. 5-year freedom from local relapse
was 98 % and overall survival was 75 %. Four patients
had acute facial numbness. Late toxicities included
three patients with retinopathy, one with carotid aneu-
rysm, and ten cases of temporal lobe necrosis espe-
cially in those with T4 tumors (Hara et al. 2008).
Taiwanese investigators reported on 54 patients given
64.8–68.4 Gy followed by 12–15 Gy SBRT boost, most
with concurrent cisplatin. Local control at 3 years was
92 % and overall survival was 85 %. Three patients
with large primary tumors had vascular bleeding
resulting in death (Chen et al. 2006).
Investigators from Hong Kong reported results for 45
patients who were offered either 20 Gy intracavitary
brachytherapy boost or fractionated SBRT following
EBRT to 66 Gy. Patients were selected due to suspi-
cion for persistent localized disease at several weeks
after EBRT completion. Median boost dose was 15 Gy,
at 6–8 Gy per fraction for 2–3 weekly fractions vs.
2.5 Gy for 8 daily fractions. At 3-year follow-up, local
failure-free control rates in the no boost, brachyther-
apy, and SBRT groups were 43, 71, and 82 % (Yau
et al. 2004).
104 S.S. Yom
Investigators in Guangzhou, China delivered SBRT to

90 patients with either persistent or recurrent disease.
For persistence, the median dose was 18 Gy in 3 frac-
tions; for recurrence, it was 48 Gy in 6 fractions. 3-year
local failure-free survival and disease-specific survival
rates were 89.4 % and 80.7 % for persistence, and 75.1
% and 45.9 % for recurrence. 17 (19 %) patients
developed severe late complications: 6 with mucosal
necrosis, 3 with brain stem necrosis, 6 with temporal
lobe necrosis, and 2 with fatal hemorrhage (Wu et al.
2007).
Locoregionally Recurrent Head and Neck

Cancer (Reirradiation)
University of Pittsburgh conducted a phase I dose-
escalation study of reirradiation for recurrent unre-
sectable head and neck squamous cell carcinoma
(HNSCC). 31 patients with oropharynx, oral cavity,
larynx, nasopharynx, and unknown primary cancers
were treated in 5 tiers ranging from 25to 44 Gy in 5
fractions over 2 weeks. Median prior dose of EBRT
was 64.7 Gy and 56 % had received prior concurrent
chemoradiation. 25 patients were evaluable for toxic-
ity, in whom no grade 3 complications were reported;
the maximally tolerated dose was not reached (Heron
et al. 2009).
Turkish investigators reported on 46 patients with
nasopharynx, oral cavity, paranasal sinus, larynx, and
hypopharynx cancers reirradiated with SBRT to
doses from 18 to 45 Gy over 1–5 fractions. 1-year
local control and survival rates were 84 and 46 %.
Eight patients had carotid artery blowout and died.
This occurred only in patients receiving 100 % of the
dose to the carotid artery and in whom tumor sur-
rounded the carotid artery by at least 180° (Cengiz
et al. 2011).
Reirradiation with Concurrent Systemic Therapy
University of Pittsburgh published a 70-patient

matched-cohort retrospective study reporting SBRT
results with or without cetuximab in previously radi-
ated HNSCC patients. Addition of cetuximab resulted
in an overall survival of 24.5 months versus 14.8 months
for patients who had SBRT alone. No grade 4–5 com-
plications occurred in either group (Heron et al. 2011).
A French (Lilly, Nancy, Nice) multi-institutional phase
II study included 60 patients with inoperable recur-
rence or new primary HNSCC (size ≤ 65 mm) in a
previously irradiated area. 80 % were oropharyngeal
tumors. 48 % had prior chemotherapy and 93 % had
more than 20 pack-year smoking history. The mean
time between prior RT and SBRT was 38 months. The
SBRT dose was 36 Gy in 6 fractions in 11–12 days,
prescribed at the 85 % IDL, given with 1 loading and
4 concurrent cycles of concurrent cetuximab. If the
spinal cord had received ≥45 Gy previously, the maxi-
mum allowed point dose was ≤6 Gy. Tumors with skin
infiltration or invading more than 1/3 of the carotid
artery were “avoided.” Among 56 patients who
completed SBRT-cetuximab with a follow-up of 11.4
months, 18 had grade 3 toxicities including mucositis,
dysphagia, fistula, induration, and fibrosis. One patient
died from hemorrhage and malnutrition. At 3 months,
response and disease control rates were 58.4 % and
91.7 %. Median survival was 11.8 months, median pro-
gression free survival was 7.1 months, and 1-year over-
all survival was 47.5 %. Per intention to treat analysis,
33 % had progressive disease (Lartigau et al. 2013).
Georgetown University investigators reported on 65
patients who were treated with SBRT, of whom 33
received concurrent chemotherapy or cetuximab.
Patients receiving <30 Gy over 5 fractions had a 29 %
response rate versus 69 % for higher doses. 2-year
local control and survival rates were 30 and 41 %. 19
106 S.S. Yom
patients experienced grade 1–3 toxicity and 7 experi-

enced severe toxicity including one death.
Chemotherapy did not improve outcomes on multi-
variable analysis, attributable to the small sample size
and heterogeneity of agents used (Unger et al. 2010).
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Chapter 7
Lung
Steve E. Braunstein, Sue S. Yom,
and Alexander R. Gottschalk
Pearls
~224,000 cases/year and 159,000 LUNG cancer deaths
in the USA (M:F ~ 1:1).
Lung cancer is the most common noncutaneous with
the greatest cancer mortality rate worldwide.
Risk of lung cancer in current smokers is 24×, and in
former smokers 6×, as compared to never smokers.
Historically, presentations were largely advanced
(symptomatic): stage I (10 %), II (20 %), III (30 %),
IV (40 %). This may shift to early stage I–II (60 %), III
(20 %), IV (20 %) with low-dose CT screening.
Low-dose CT screening currently recommended by
USPSTF for adults 55–80 years old with ≥30 pack-year
smoking history, currently smoking or having quit
within the past 15 years.
Poor outcomes for untreated stage I NSCLC: median
OS 9 months, 5 years OS 7 %.
S.E. Braunstein () • S.S. Yom • A.R. Gottschalk

San Francisco, 1600 Divisadero Street, Suite H1031,
e-mail: steve.braunstein@ucsf.edu

110 S.E. Braunstein et al.
Lobectomy has been considered standard of care for

early-stage, medically operable NSCLC, with 5 years
OS 60–70 %. However, recent studies suggest equiva-
lent efficacy of sublobar resection, including wedge
resection for small peripheral tumors, in the era of
CT-based diagnosis.
Of note, historically ~15 % of cT1-2 N0 have + LN,
which may be underappreciated by nonsurgical man-
agement approaches. However, with PET and CT stag-
ing this may be diminished.
Conventionally fractionated EBRT approaches to
early-stage lung cancer associated with poor LC (20–
70 %) and OS (20–60 %) at 3 years.
Improved outcomes with dose escalation and hypo-
fractionation suggested by multiple studies in EBRT,
though continues to be an area of uncertainty for
locally advanced disease.
Current studies of SBRT for early-stage NSCLC show
LC ~85–95 % and OS ~60–80 % at 3 years. Distant
failure rate ~20 %.
NSCLC dose calculations for tumor control employ
[alpha]/[beta] = 10
Improved early-stage NSCLC outcomes associated
with SBRT dose and fractionation schemas achieving
BED10 ≥ 100 Gy.
Metachronous primary NSCLC arises in 4–10 % of
early-stage patients within 5 years of initial treatment.
Stage III patients treated with conventional chemora-
diation experience 25 % rate of in-field recurrence.
Complete metastasectomy of lung lesions of various
malignant primary histologies is associated with 5
years OS 20–40 %.
Workup
H&P, including performance status, weight loss, and
smoking status.
Review of symptoms
7. Lung 111
Most early-stage NSCLC are asymptomatic.

More advanced presentations include cough, dys-
pnea, hemoptysis, post-obstructive pneumonia,
pleural effusion, pain, hoarseness (left recurrent
laryngeal nerve), SVC syndrome, clubbing,
superior sulcus (Pancoast) tumor triad of
shoulder pain, brachial plexopathy, and Horner’s
syndrome.
Laboratories
CBC, BUN, Cr, LFTs, alkaline phosphatase, and
LDH.
Imaging
Chest, abdomen, and pelvis staging CT with con-
trast (r/o liver and adrenal metastases).
PETCT (>90 % negative predictive value for nodal
involvement, but low sensitivity for adenocarci-
noma in situ (AIS); unclear association of max SUV
with SBRT outcomes).
MRI brain for LN+, stage III-IV, and/or if neuro-
logic symptoms on presentation.
MRI thoracic inlet for superior sulcus tumors for
assessment of brachial plexus and vertebral
involvement.
Pathology
CT-guided biopsy of peripheral N0 lesions.
Mediastinoscopy or bronchoscopic biopsy for cen-
tral tumors and/or N+ disease.
Thoracentesis for pleural effusions.
Molecular testing for Kras activation, EGFR muta-
tion, ROS and ALK gene rearrangements.
Pulmonary function testing for presurgical and prera-
diotherapy evaluation.
Medically inoperable is generally FEV1 <40 % or
<1.2 L, DLCO <60 %, FVC <70 %.
SBRT is currently employed in NSCLC. SBRT has no
established role in small cell lung cancer.
Early-stage NSCLC managed by local therapy, with
surgical resection as standard of care historically, and
SBRT approaches most frequently employed for
node-negative, medically inoperable and increasingly
for select (high-risk and elderly) operable candidates.
The role of adjuvant chemotherapy in SBRT-treated
T2N0 disease is not established in any way.
Multimodal therapy is employed for locally advanced
disease.
Most established SBRT criteria include N0 patients
with <5 cm, peripherally located tumors, but tumors
may be more cautiously treated with expanded criteria
of larger size (<7 cm), central location, multiple syn-
chronous lesions, and chest wall invasion (T3N0) with
historically inferior results.
SBRT has a developing role as a boost following defini-
tive chemoradiation in management of locally advanced
NSCLC, for re-irradiation of locally recurrent disease,
and for treatment of intrathoracic oligometastases from
various primary histologies (commonly stage IV
NSCLC, sarcoma, renal cell carcinoma, thyroid, or
colorectal cancer) (Table 7.1).

Tumor motion may be 2–3 cm in peri-diaphragmatic
regions of the lower lung. Motion management strate-
gies include respiratory gating, coaching with audio-
visual feedback, breath-hold techniques, abdominal
compression, and intrafraction tumor tracking real-
time imaging techniques with dynamic beam and/or
couch compensation.
7. Lung 113
Table 7.1 Treatment recommendations for NSCLC and pulmo-

nary oligometastases
Presentation Resectability Recommended treatment
T1-2N0 Operable Lobectomy (preferred over
segmentectomy or wedge
resection) or SBRT
Inoperable SBRT (may consider RFA/
Cryotherapy)
II (T2bN0, Operable Surgery → chemo (>4 cm)
T1-2N1, T3N0) Inoperable ChemoRT → ±chemo or hypofx
EBRT → ±chemo
IIIA Operable ChemoRT → restage → surgery →
chemo or Chemo → restage →
surgery → chemo ± RT
Inoperable ChemoRT → ±chemo
IIIB Inoperable ChemoRT → ±chemo
Recurrent Operable EBRT/SBRT/resection
for limited local
recurrence → systemic therapy
Inoperable EBRT/SBRT/RFA/cryo for
limited recurrence → systemic
therapy
Pulmonary Operable Lobectomy/wedge resection
oligometastases or SBRT or hypofractionated
EBRT (for larger lesions,
>5 cm) → systemic therapy
Inoperable SBRT, RFA, cryo, or hypofx
EBRT (preferred for larger
lesions, > 5 cm) → systemic
therapy
Thin-cut CT (≤1.5 mm) thickness recommended. 4DCT

or maximal inspiratory and expiratory phase CTs or slow
CT recommended to assess target and critical structure
internal motion. Free-breathing helical or mean intensity
projection CT should be used for dose calculation.
iGTV contoured from Maximum Intensity Projection
(MIP) generated from 4DCT. MIP should be used
judiciously in tumors adjacent to diaphragm or chest
wall, with additional imaging as needed to fully dis-
criminate the target from surrounding normal tissue
with similar CT tissue density.
GTV/iGTV = tumor visible on CT lung window.

CTV/ITV = GTV/iGTV + 0–10 mm (in RTOG proto-
cols, GTV and CTV have been considered identical on
CT planning with zero expansion margin added).
PTV = CTV/ITV + 3–10 mm (dependent upon avail-
able center-specific IGRT and motion management
capabilities). Current RTOG guidelines are:
Non-4DCT planning, PTV = GTV + 5 mm axial and
10 mm longitudinal anisotropic margins.
4DCT planning, PTV = ITV + 5 mm isotropic
margin.
Dose to proximal OARs attributed to compact inter-
mediate dose region outside of the CTV/ITV region,
generally reduced with increased beams and angles, as
well as minimization of margins on target.
Treatment planning guidelines (adapted from
RTOG 0618).
VRx dose ≥95 % PTV, V90 ≥99 % PTV.
High dose region (≥105 % Rx dose) should fall
within the PTV.
Conformality Index goal ≤1.2.
Heterogeneity correction algorithms are increasingly
routinely used for planning (anisotropic analytical
algorithm, collapsed cone convolution, Monte Carlo,
etc.). Pencil-beam algorithms that overestimate dose in
heterogeneous tissue are generally not recommended.
Phantom-based QA on treatment plans.
Dose Prescription
Dose and fractionation directed by adjacent normal

tissue RT toxicity constraints with goal tumor
BED10 > 100. Adaptive dosimetry for histology-, vol-
ume-, location-, and context-based lesions (primary vs.
metastatic) are under investigation.
Current dose fractionation schema largely employs
1–5 fractions.
7. Lung 115
Fig. 7.1. SBRT planning for a central early-stage NSCLC. Beam

distribution shown on 3D anatomy reconstruction (left) and dose
distribution for 50 Gy given in 5 fractions (right)
Peripheral Lung Tumors

Common accepted schemas: 25–34 Gy × 1 fraction,
18 Gy × 3 fractions, 12 Gy × 4 fractions, 10 Gy × 5
fractions.
Central Lung Tumors
We recommend: 10 Gy × 5 fractions (BED10 dose
limited to reduce toxicity of central structures:
large airways, heart, esophagus, and spinal cord).
See Fig. 7.1.
Dose typically prescribed 60–90 % IDL, with ≥95 %
PTV coverage by prescription dose.
Composite planning should be employed in cases of
regional lung re-irradiation with appropriate BED
conversion for dose summation.
Dose Limitations
See Table 7.2, assuming no prior regional radiotherapy

(TG101, Benedict et al., 2010; RTOG 0618).
Table 7.2 Recommended dose constraints for SBRT lung lesion

target planning
Structure Fractions Constraints
Lung 1 V7 < 1500 cc
3 V11.6 < 1500 cc
5 V12.5 < 1500 cc
Central airway 1 V10.5 < 4 cc, Dmax 20.2 Gy
3 V15 < 4 cc, Dmax 30 Gy
5 V16.5 < 4 cc, Dmax 40 Gy
Chest wall 1 V22 < 1 cc, Dmax 30 Gy
3 V28.8 < 1 cc, Dmax 36.9 Gy
5 V35 < 1 cc, Dmax 43 Gy
Heart 1 V16 < 15 cc, Dmax 22 Gy
3 V24 < 15 cc, Dmax 30 Gy
5 V32 < 15 cc, Dmax 38 Gy
Esophagus 1 V11.9 < 5 cc, Dmax 15.4 Gy
3 V17.7 < 5 cc, Dmax 25.2 Gy
5 V19.5 < 5 cc, Dmax 35 Gy
Brachial plexus 1 V14 < 3 cc, Dmax 17.5 Gy
3 V20.4 < 3 cc, Dmax 24 Gy
5 V 27 < 3 cc, Dmax 30.5 Gy
Spinal cord 1 V10 < 0.35 cc, Dmax 14 Gy
3 V18 < 0.35 cc, Dmax 21.9 Gy
5 V23 < 0.35 cc, Dmax 30 Gy
Skin 1 V23 < 10 cc, Dmax 26 Gy
3 V30 < 10 cc, Dmax 33 Gy
5 V36.5 < 10 cc, Dmax 39.5 Gy
Dose Delivery
Dose delivered in consecutive daily or every other day

fractions as per current NRG protocols.
Setup may be isocentric or non-isocentric depending
upon SBRT delivery system.
Verification by kV XR or CBCT, aligned to visualized
tumor or surrogate.
Intrafraction dose delivery adjustment by motion
management and IGRT systems as discussed above.
7. Lung 117

Common acute toxicities (<6 weeks):
Fatigue
Generally early-onset and self-limiting.
Sustained fatigue may be related to cardiopulmo-
nary dysfunction (CHF, CAD, COPD, etc.) and war-
rants further work up.
Cough/dyspnea
Low-grade cough common secondary to RT-related
intrapulmonary inflammation. Antitussive pharma-
cotherapy for mild symptoms.
Severity of shortness of breath may be related to
baseline lung function and associated comorbidi-
ties. For patients with moderate to severe symptoms
or significant baseline comorbidities (COPD, ILD,
CHF, etc.), recommend follow-up with pulmonol-
ogy and/or cardiology.
Chest pain
May be related to regional pleuritis and/or pericar-
ditis and is generally self-limited.
Analgesic pharmacotherapy recommended.
Pneumonitis
Associated with increased dose volume (V20
<10 %), smoking history (current/former), age,
prior use of steroids, and comorbidity index on mul-
tiple studies.
Generally subacute onset (>2 weeks), associated
with cough, dyspnea, hypoxia, and fever.
If symptomatic, treat with prednisone (1 mg/kg/d)
or 60 mg/d and trimethoprim/sulfamethoxazole
for PCP prophylaxis. Symptomatic relief may be
rapid but slow steroid taper is critical for durable
symptom resolution.
Esophagitis
Increased risk with treatment centrally located
tumors, and is generally self-limited to several
weeks after treatment.
Local or systemic analgesic pharmacotherapy (lido-
caine, NSAIDs, opioids) ± proton pump inhibitor
based on severity of symptoms.
Dermatitis
Chest wall entrance and exit doses can be reduced
with increased numbers of beams to minimize
radiation dermatitis.
Mild to moderate skin reaction treated with sup-
portive care, including topical moisturizers, analge-
sics, low-dose steroids, and antimicrobial salves.
Common late toxicities (>6 weeks):
Persistent cough/dyspnea
Recommend consultation with pulmonary medi-
cine for consideration of long-term bronchodilator
and anti-inflammatory therapy.
Radiation pneumonitis
Most commonly observed at ~6 weeks.
As above, recommend steroids with gradual taper
for symptomatic patients
Brachial plexopathy
Apical lung tumors associated with greater risk of
brachial plexus injury.
May present with neuropathic pain as seen in
Lhermittes syndrome or with motor/sensory
changes in the upper extremities.
MRI of brachial plexus and upper spine may be
diagnostic and rule out tumor recurrence.
Limited treatment options include supportive care
and occupational therapy.
Chest wall pain and rib fracture
More common in patients with peripheral lesions.
Supportive care indicated.
7. Lung 119
Radiation skin ulcer

For persistent non-healing skin lesions, consider
hyperbaric oxygen therapy and tocopherol
pharmacotherapy.
Esophageal stricture and tracheoesophageal fistula
Historically rare complication observed with treat-
ment of mediastinal lymphadenopathy in locally
advanced lung cancer.
Even less likely with SBRT, if airway and esopha-
geal constraints maintained, with exception of
re-irradiation setting.
Vasculopathy
Vascular erosion may lead to limited hemoptysis or
massive hemorrhage and death (seen in re-irradia-
tion setting of central lesions).
CT or PETCT every 3–4 months × 3 years, every 6
months × 2 years, every 12 months thereafter for rou-
tine follow-up.
Assessment with RECIST criteria of limited utility
due to wide spectrum of evolving radiographic fea-
tures following SBRT including diffuse and patchy
GGO, consolidation, and/or fibrosis.
In general, radiographic changes include early inflam-
matory response (≤3 months) followed by resolution
of FDG activity and late fibrosis (>6 months) in area
of treated lesion which is often dynamic and may
evolve over several years.
Persistent increase in size and density of treated tumor
on interval CTs in the early post-treatment setting
(<12 months) or new densities at later times (>12 months)
should be considered suspicious for recurrence, with
recommendation for increased frequency of CT, interval
PET scan, and consideration of biopsy and/or surgical or
radiotherapy salvage procedure.
Role of molecular imaging and circulating tumor
markers is under investigation.
Evidence
Primary Lung Cancer
Evidence widely supports efficacy and safety of SBRT

in early-stage NSCLC, with optimal patient selection
criteria and dose schema emerging as studies mature.
CALGB 39904 (Bogart et al. 2010). Phase I dose-
escalation study of 39 stage I (≤4 cm) NSCLC patients.
70 Gy in 29 decreased to 17 fractions. 92.3 % actuarial
control, 82.1 % actuarial distant control. No late grade
3 or 4 toxicity.
Onishi et al. (2004). Initial report of retrospective
Japanese multi-institutional series of 245 patients with
stage I NSCLC treated with SBRT 18–75 Gy in 1–22
fractions with a median follow-up of 24 months. Grade
≥3 toxicity 2.4 %. LR at 3 years for BED ≥ 100 vs.
BED < 100 was 8.1 % vs. 26.4 %, p < 0.05 and OS was
88.4 % vs. 69.4 %, p < 0.05, establishing BED ≥ 100 as
prescribing criterion.
Nordic Study Group (Baumann et al. 2009). Phase II
study of SBRT in 57 patients with medically inoperable
early-stage peripheral tumors (40 stage IA, 17 stage
IB), treated with 45–66 Gy in 3 fractions. Estimated 3
year LC and OS were 88.4 % and 59.5 %, respectively.
Distant metastatic rate 16 %. Risk of any failure
increased in T2 vs. T1 tumors (41 % vs. 18 %, p = 0.027).
RTOG 0236 (Timmerman et al. 2010, Stanic et al.
2014). Phase II multicenter trial of 55 patients with
medically inoperable early-stage (<5 cm) peripheral
NSCLC (44 stage IA, 11 stage IB), treated with
54 Gy in 3 fractions SBRT. Three year primary tumor
and involved lobe control was 98 %. Rate of distant
failure 22 % at 3 years. OS 56 % at 3 years. Grade 3
and 4 toxicities were 12.7 % and 3.5 %, respectively.
Poor baseline PFT not predictive of SBRT-related
toxicity.
7. Lung 121
Timmerman et al. (2006), Farikis et al. (2009). Phase II

study of SBRT at Indiana University for T1-2N0 medi-
cally inoperable NSCLC patients (n = 70), 60–66 Gy in
3 fractions. LC and OS at 3 years were 88.1 % and
42.7 %, respectively. Grade ≥3 toxicity rates of 10.4 %
peripheral vs. 27.3 % central over a median follow-up
of 50.2 months (p = 0.088).
JCOG 0403 (Nagata et al. 2012). Phase II trial of SBRT
in early-stage NSCLC, stratified by medically operable/
inoperable. In medically inoperable arm, 100 patients
with stage IA disease received 48 Gy in 4 fractions. LC
and OS at 3 years were 88 % and 59.9 %, respectively.
For 64 medically operable patients, LC and OS at 3
years were 86.0 % and 76.0 %, respectively. Grade 3
pneumonitis 7 %, overall grade 4 toxicity 2 %.
RTOG 0618 (Timmerman et al. 2013). Phase II trial of
33 patients with medically operable early-stage periph-
eral NSCLC (<5 cm), treated with 60 Gy in 3 fractions.
Completed accrual in 2010 with results presented at
ASCO 2013 showing estimated 2 years primary tumor
failure rate of 7.8 %, with a median follow-up of 25
months. Local failure, including ipsilateral lobe, was
19.2 %. PFS and OS at 2 years were estimated at
65.4 % and 84.4 %. Grade 3 toxicity was 16 %.
RTOG 0813. Phase I/II dose-escalation trial of medi-
cally inoperable centrally located (<2 cm of proximal
bronchial tree) early-stage NSCLC (<5 cm). At the
time of accrual completion, dose escalated to 60 Gy in
5 fractions. Closed to accrual at 120 patients in 2013.
Results are pending.
RTOG 0915 (Videtic et al. 2013). Phase II randomized
trial of 34 Gy in 1 fraction vs. 48 Gy in 4 fractions for
medially inoperable early-stage peripheral NSCLC
(<5 cm). Study completed accrual in 2011 with 94
patients. At 1 year, LC 97.1 % vs. 97.6 %; OS 85.4 % vs.
91.1 %, and PFS 78.0 % vs. 84.4 %. Adverse events were
9.8 % vs. 13.3 %. Based on the favorable toxicity, the
34 Gy in 1 fraction arm will be compared to the 54 Gy

in 3 fractions arm of RTOG 0236 in a phase III setting.
Hoppe et al. (2008). Study of 50 stage I NSCLC
patients treated with SBRT 60 Gy in 3 fractions or
44–48 Gy in 4 fractions with a median follow-up of 6
months. Skin toxicity was 38 % grade 1, 8 % grade 2,
4 % grade 3, and 2 % grade 4. Reduced number of
beams, proximal distance to chest wall, and skin dose
≥50 % prescription dose were associated with
increased risk of skin toxicity.
Mutter et al. (2012). Retrospective study of 128 early-
stage NSCLC patients receiving SBRT 40–60 Gy in
3–5 fractions. With a median follow-up of 16 months,
grade ≥2 chest wall toxicity was 39 % estimated at 2
years. On dosimetric analysis, grade ≥2 chest wall pain
was associated with a V30Gy >70 cm3 within a 2 cm
2D-ipsilateral chest wall expansion.
ACOSOG Z4099/RTOG 1021. Phase III trial of SBRT
vs. sublobar resection for high-risk operable, early-
stage peripheral NSCLC (<3 cm). Terminated for poor
accrual.
ROSEL Trial (VUMC, NCT00687986). Phase III trial
of SBRT (60 Gy in 3 or 5 fractions) vs. surgery for stage
IA peripheral NSCLC. Terminated for poor accrual.
STARS Trial (MDACC, NCT00840749). Phase III trial
of SBRT 60 Gy in 3–4 fractions based on lesion loca-
tion vs. surgery for stage I NSCLC. Terminated for
poor accrual.
Grills et al. (2010). Retrospective comparison of 124
patients (95 % medically inoperable) T1-2 N0 NSCLC
receiving wedge resection (n = 69) vs. SBRT (n = 58),
48–60 Gy in 4–5 fractions. No statistically significant
differences in LRR (27 % wedge vs. 9 % SBRT,
p > 0.16) or CSS (94 % wedge vs. 93 % SBRT, p = 0.53)
noted at a median follow-up of 30 months. OS favored
wedge resection (87 % wedge vs. 72 % SBRT, p = 0.01).
Crabtree et al. (2010). Retrospective comparison of
stage I NSCLC patients receiving either surgery
(n = 462) or SBRT (n = 76) for definitive care. Surgical
7. Lung 123
candidates had fewer medical comorbidities. Thirty-

five percent of surgical patients were upstaged on final
pathology. OS 5 years 55 % surgery and OS 3 years
32 % with SBRT. In propensity matched analysis, no
statistically significant difference in LC (88 % vs.
90 %) and OS (54 % vs. 38 %) at 3 years in surgery vs.
SBRT groups.
SEER-Medicare analysis (Shirvani et al. 2012).
Comparative outcomes of stage I NSCLC patients ≥60
years old, which demonstrated overall ranked out-
comes as lobectomy > sublobar resection > SBRT > con-
ventional EBRT > observation. However, as treatment
outcomes were likely influenced by patient selection
and comorbidities, there was no difference in OS
between SBRT and surgical modalities on propensity
matched analysis, and EBRT remained inferior to
SBRT.
Shah et al. (2013a, b). Cost-effectiveness comparison
of surgical resection vs. SBRT for stage I NSCLC
patients >65 years. For marginally operable patients,
SBRT was most cost effective with a mean cost and
quality-adjusted life expectancy of $42 k/8.0 years vs.
lobectomy at $49 k/8.9 years. However, for completely
operable candidates, lobectomy was found more cost
effective, having an incremental cost-effectiveness
ratio of $13 K/quality-adjusted life year.
Table 7.3 summarizes several multiple primarily retro-
spective series indicating local control rates of 85–95 %
at 3–5 years, and overall survival rates of 50–95 % at 3–5
years for early-stage NSCLC managed with SBRT.
Some series include limited numbers of recurrent and
metastatic patients.
Role as Boost for Locally Advanced Lung Cancer
Studies have suggested a role for dose escalation as

part of conventional chemoradiation in locally
Table 7.3 Selected studies of SBRT treated NSCLC patients
Study Patients Treatment LC/OS Notes
Onishi et al. 2226 patients stage I 32–70 Gy in 3–12 fractions, 3 years LC/OS 85 %/72 % 2.9 % grade
JRS-SBRTSG NSCLC median BED 107 Gy 3 years LPFS 87 % T1, 72 % T2 ≥3
(IJROBP 2013) (range 58–150 Gy) 3 years OS 75 % BED ≥ 100 Gy
vs. 63 % BED < 100 Gy (p < 0.01)
Grills et al. 482 patients (505 20–64 Gy in 1–15 fractions, 2 years LC/OS 94 %/60 %, 7 % grade ≥2
Multi- tumors) T1-3N0 median 54 Gy in 3 LC 96 % BED ≥ 105 vs. 85 % pneumonitis
institutional NSCLC, fractions BED < 105 (p < 0.001) 3 % rib
(JTO 2012) 87 % medically fracture
inoperable
Shibamoto 180 patients stage I Volume-adapted 3 years LC/OS 13 % grade ≥2

et al. Japan NSCLC (120 medically 44 Gy in 4 fractions 83 %/69 %, OS 74 % operable vs. pneumonitis
(IJROBP 2013, inoperable, 60 operable) <1.5 cm, 48 Gy in 4 59 % inoperable, LC 86 % ≤3 cm
Cancer 2011) fractions 1.5–3.0 cm, 52 Gy vs. 73 % >3 cm
in 4 fractions >3.0 cm 5 years LC/OS
82 %/68 %
Uematsu et al. 50 patients T1-T2N0 50–60 Gy in 5–10 fractions 3 years LC/OS 4 % rib
Japan (IJROBP NSCLC (21 medically (18 patients received 94 %/66 % fracture
2001) inoperable, 29 operable) 40–60 Gy in 20–33 (86 % OS in medically operable
fractions prior to SBRT) subgroup)
Stephans et al. 94 patients stage I 50 Gy in 5 fractions, 1 year LC/OS 2.2 % grade 2
Cleveland NSCLC medically 60 Gy in 3 fractions 97 %/83 % 50 Gy in 5 fractions, pneumonitis
Clinic (JTO inoperable 100 %/77 % 60 Gy in 3 fractions 10 % grade
2009) 1–2 chest wall
toxicity
Olsen et al. 130 patients early-stage Peripheral tumors 54 Gy in 2 years LC 16 % chest
Wash U. NSCLC 3 fractions, central tumors 91 % (54 Gy in 5 fractions) wall pain
(IJRBOP 2011) 45–50 Gy in 5 fractions 100 % (50 Gy in 5 fractions) (grade 1–3)
50 % (45 Gy in 5 fractions) 3 % grade 2
2 years OS pneumonitis
85 % operable
61 % inoperable
Modh et al. 107 central tumors (83 45–50 Gy in 4–5 Gx 2 years LC/OS 72 %/56 % 12 % grade ≥ 3
MSKCC primary NSCLC, 10
(IJROBP 2013) recurrent, 14 metastatic)
Trakul et al. 111 patients (100 Volume-adapted iSABR 1 year LC/OS 4.% grade 3
Stanford primary NSCLC, 11 (GTV < 12 ml → BED < 100, 94 %/90 % in primary NSCLC
(IJROBP metastatic) GTV ≥ 12 ml → BED ≥ 100) subgroup,
2012a, b) 18–30 Gy in 1 fraction, 15 % DM rate,
50–60 Gy in 4–5 fractions no difference in LC/OS by BED
Taremi et al. 108 patients, stage I Peripheral tumors 48 Gy 4 years LC/OS 92 %/30 % 11 % grade 3
Canada NSCLC medically in 4 fractions or 54–60 in 4 years distant DFS 83 %
(IJROBP 2012) inoperable, 24 % w/o 3 fractions, central tumors
path diagnosis 50–60 Gy in 8–10 fractions
(continued)
Lagerwaard 206 patients T1-2N0 Risk-adapted 60 Gy in 3 2 years LC/OS 83 %/64 % 3 % grade ≥3
et al. VUMC fractions (T1), 5 fractions (LC 92 % T1, 71 % T2) pneumonitis
(IJROBP 2008) (T1 near CW or T2), or 8 2 years distant PFS 77 % 2 % rib
fractions (central) fracture
1 % late CW
pain
Badiyan et al. 120 patients (early-stage 54 Gy in 3 fractions 3 years LC/OS Not reported
Wash U. (RO NSCLC and AIS) 100 %/35 % AIS,
2013) 86 %/47 % NSCLC
Bradley et al. 91 patients stage I/ Peripheral tumors 54 Gy in 2 years LC/OS 3 % grade 2
Wash U. II NSCLC, medically 3 fractions, central tumors 86 %/70 % pneumonitis
(IJROBP 2010) inoperable 45 Gy in 5 fractions 4 % rib fracture
1 % brachial
plexopathy
Palma et al. 176 patients stage I 60 Gy in 3–5 fractions 3 years LC/OS 3 % grade 3
VUMC NSCLC, severe COPD 89 %/47 %
(IJROBP 2012)
Chang et al. 130 patients stage I 50 Gy in 4 fractions 2 years LC/OS 12 %
MDACC (RO NSCLC 98 %/78 % grade 2–3
2012) pneumonitis
Griffioen et al. 62 patients with multiple 54–60 Gy in 3–8 fractions 2 years LC/OS 4.8 % grade 3
VUMC (RO synchronous primary 84 %/56 %
2013) early-stage NSCLC
7. Lung 127
advanced lung cancer, with current focus on reduced

volume boost, to minimize normal lung toxicity, for
which SBRT may be of utility.
Karam et al. (2013). Retrospective series of 16 primar-
ily stage III NSCLC (38 % IIIA, 56 % IIIB) patients
who received conventional chemoradiation to a
median dose of 50.4 Gy (range 45–60 Gy) followed by
an SBRT boost (20–30 Gy in 5 fractions) to residual
disease on interval planning CT. LC and OS at 1 year
were 76 % and 78 %, respectively. Grade ≥2 pneumo-
nitis occurred in 25 % of patients.
Feddock J et al. (2013). Prospective feasibility trial at
Univ Kentucky with 35 stage II-III NSCLC patients
treated with conventional chemoradiation to 60 Gy
followed by an SBRT boost of 20 Gy in 2 fractions or
19.5 Gy in 3 fractions (for central tumors) limited to
persistent primary tumor (≤5 cm without additional
residual disease) on interval CT ± PET. With a median
follow-up of 13 months, LC was 82.9 %. Acute and late
grade 2–3 pneumonitis were 17 % and 9 %, respec-
tively. Two patients had large cavitary recurrences
associated with likely hemorrhagic death, which may
be considered grade 5 toxicities.
Chemotherapy in Early-Stage Lung Cancer
The role and timing of adjuvant chemotherapy for

SBRT-treated NSCLC remains unclear, although sev-
eral surgical series have shown a survival benefit with
adjuvant chemotherapy in early-stage lung cancer.
CALGB 9633 (Strauss et al. 2008). Phase III trial of
344 pT2N0 patients randomized to observation vs.
adjuvant chemotherapy (paclitaxel/carboplatin
q3w × 4c) following lobectomy or pneumonectomy.
With a median follow-up of 74 months, there was no
difference in OS. However, exploratory analysis dem-
onstrated improved OS in patients with tumors ≥4 cm
(HR 0.69, p = 0.043).
LACE (Lung Adjuvant Cisplatin Evaluation) meta-

analysis (Pignon et al. 2008; JCO). Meta-analysis of
five trials of 4584 patients with stage I-III NSCLC
receiving cisplatin-based adjuvant chemotherapy after
completed surgical resection. At 5 years, absolute OS
benefit of 5.4 % with adjuvant chemotherapy. However,
subset analysis showed benefit limited to stage II and
III patients.
Preoperative chemotherapy meta-analysis (NSCLC
Meta-analysis Collaborative Group, 2014). Analysis of
15 RCT, with a total of 2385 primarily stage IB-IIIA
NSCLC patients, demonstrated benefit of preoperative
chemotherapy on survival (HR 0.87, p = 0.007), with an
absolute benefit of 5 % at 5 years across all stages.
Postoperative chemotherapy meta-analyses (NSCLC
Meta-analyses Collaborative Group). Meta-analysis of
surgery plus chemotherapy vs. surgery alone based upon
34 trial comparisons with 8447 stage I-III NSCLC
patients. Adjuvant chemotherapy associated with OS
benefit (HR 0.86, p < 0.0001), with 4 % absolute increase
in survival at 5 years. Subset analysis showed an absolute
benefit of 3 % and 5 % with adjuvant chemotherapy for
stages IA and IB, respectively.
Metastatic Lung Cancer
Multiple studies suggest safety and efficacy of SBRT in

management of oligometastatic disease, in populations
with modest to poor KPS, many having received prior
multimodal therapy. Optimal volume-based and
histology-specific dose schemas are under investigation.
Rusthoven et al. (2009). Multi-institutional phase I/II
dose-escalation study of 38 patients with 1–3 lung
metastases with cumulative tumor diameter <7 cm.
Study consisted of SBRT dose escalation from 48 to
60 Gy in 3 fractions. Grade 3 toxicity was 8 %. With a
median follow-up of 15.4 months, actuarial 1 and 2
years LC was 100 % and 96 %, respectively. OS 39 %
at 2 years.
7. Lung 129
Table 7.4 Selected studies of SBRT for metastatic lung lesions

Study Patients Treatment LC/OS Toxicity
Singh et al. 34 patients 40–60 Gy 2 years LC/ No grade
Rochester with 1–5 in 5 OS ≥2
(J Thorac metastatic fractions 88 %/44 %
Dis 2014) lesions
Johnson 90 patients 50 Gy 2 years 4 % ≥ grade
et al. UCSF with central in 5 LC/OS 3
(Oncology tumors fractions 82 %/32 %
2014) (72 with metastatic
metastatic subgroup
lesions)
Baschnagel 32 patients 48–60 Gy 2 years LC/ 16 % grade
et al. Wash with 1–3 in 4–5 OS 3
University metastatic fractions 92 %/76 % no grade
(Clin Oncol lesions ≥4
2013)
Hamamoto 62 patients 48 Gy 2 years LC/ Not
et al. Japan (10 with in 4 OS reported
(JJCO 2009) metastatic fractions 25 %/86 %
lesions, 52 in
with stage I metastatic
NSCLC) subgroup
(vs.
88 %/96 %
in primary
NSCLC
patients,
p < 0.0001)
Norihisa 34 patients 48 Gy 2 years 12 % grade
et al. Japan with 1–2 in 4 LC/OS 2
(IJROBP metastatic fractions, 90 %/84 % 3 % grade
2008) lesions 60 Gy 3
in 5
fractions
Wulf et al. 61 patients 30– 1 year LC/ 3 % grade
Germany (41 with 37.5 Gy OS 2
(IJROBP metastatic in 3 80 %/85 % no grade
2004) lesions, fractions, metastatic ≥3
20 with 26 Gy in subgroup
stage I-II 1 fraction
NSCLC)
(continued)

Study Patients Treatment LC/OS Toxicity
Lee et al. 28 patients 30–40 Gy 2 years LC/ No grade
S. Korea (19 with in 3–4 OS ≥2
(Lung metastatic fractions 88 %/88 %
Cancer lesions) metastatic
2003) subgroup
Nakagawa 15 patients 15– Median LC 1 patient
et al. Japan (14 with 24 Gy × 1 8 months with late
(IJROBP metastatic fraction Median OS toxicity
2000) lesions) 9.8 months
Le et al. (2006). Single-fraction SBRT phase I dose-

escalation study of 32 patients (21 T1-2 N0 NSCLC, 11
with oligometastatic lung tumors). Dose escalation was
from 15 to 30 Gy. LC for all tumors at 1 year was 91 %
for >20 Gy and 54 % for <20 Gy (p = 0.03). For meta-
static tumors specifically, LC and OS at 1 year were
25 % and 56 %, respectively. Toxicity included 4 cases
of grade 2–3 pneumonitis, 1 pleural effusion, and 3 pos-
sible treatment-related deaths.
Ernst-Stecken et al. (2006). Phase I/II study of SBRT
dose escalation in 21 patients (3 primary stage I NSCLC,
18 metastatic). Dose escalation 35–40 Gy in 5 fractions.
One instance of grade 3 toxicity reported. Median fol-
low-up was 6.3 months. LC 81 % at 13 months.
Table 7.4 summarizes multiple retrospective institu-
tional series indicating local control rates of largely
80–90 % at 2 years, and overall survival rates of
30–85 % at 2 years for patients with pulmonary metas-
tases managed with SBRT. Most series include patients
having previously received multimodal therapy and
with both primary controlled and uncontrolled disease.
As noted, several series also include both primary and
metastatic disease.
7. Lung 131
Recurrence/Re-irradiation
Several institutional series reporting SBRT experience

for oligometastatic intrathoracic tumors have included
patients with recurrent lung cancer or metachronous
primary NSCLC.
Reyngold et al. (2013). Retrospective series of 39
patients at MSKCC treated with SBRT (median
BED10 70.4 Gy, range 42.6–180 Gy) for recurrence or
new primary cancer after prior conventionally frac-
tionated EBRT (median dose 61 Gy) for chiefly
NSCLC or scc. Median RFS was 13.8 months and
median survival was 22 months. Grade 2 and 3 pulmo-
nary toxicities were 18 % and 5 % respectively (dys-
pnea, hypoxia, cough, and pneumonitis). One patient
had grade 4 skin ulceration.
Trakul et al. (2012a, b). Retrospective series of 15
patients treated at Stanford University LC 65 % at 1
year vs. 92 % for 135 patients receiving SBRT in pri-
mary setting. OS 80 % at 1 year vs. 92.9 % for primary
SBRT group. Shorter interval between treatments was
associated with increased risk of recurrence. One
instance of chest wall toxicity observed in re-irradiated
group.
Peulen et al. (2011). Retrospective analysis from the
Netherlands of SBRT re-irradiation in 32 patients who
received prior thoracic SBRT (30–40 Gy in 2–4 frac-
tions), with re-irradiation (30–40 Gy in 2–5 fractions)
defined as 50 % PTV overlap. Grade 3–4 toxicity was
25 % and 3 patients suffered grade 5 toxicity, with death
from hemorrhage following re-irradiation of the central
chest. LC was 52 % at 5 months. OS 59 % at 1 year.
Kelly et al. (2010). Retrospective study of 36 patients
at MDACC receiving SBRT (50 Gy in 4 fractions) for
recurrent NSCLC after prior conventionally fraction-
ated EBRT (median dose 62 Gy). Thirty-three percent
grade 3 toxicity (pneumonitis, cough, chest wall ulcer,
esophagitis). LC and OS at 2 years, 92 % and 59 %,
respectively.
Liu et al. (2012). Updated data for 72 patients at

MDACC who received SBRT (50 Gy in 4 fractions)
for recurrent or metachronous second primary NSCLC
after prior thoracic conventionally fractionated EBRT
(median dose 63 Gy). LC and OS at 2 years were 42 %
and 74 %, respectively. Grade ≥3 pneumonitis was
observed in 21 % of re-irradiated patients. Predictors
of pneumonitis included ECOG PS 2–3, pre-SBRT
FEV1 ≤ 65 %, V20 ≥ 30 % in composite plan, and prior
bilateral mediastinal PTV (all p < 0.03).
Senthi et al. (2013). Retrospective review of 27 patients
treated with pneumonectomy for prior NSCLC, with
second early-stage primary NSCLC who then received
RT for definitive management (including 20 SBRT
patients treated with 54–60 Gy in 3–8 fractions). LC 3
years was 8 %. MS 39 months. Grade ≥3 pneumonitis
seen in 15 % SBRT-treated patients.
Technique
Seppenwoodle et al. (2002). Analysis of lung tumor

motion via fiducial tracking in 20 patients during
radiotherapy. Tumor motion was greatest in cranial-
caudal axis for lower lobe lesion (12 ± 2 mm). Time
averaged tumor position was closer to the exhale posi-
tion, and appears more stable in the exhale vs. inhale
phases during intrafraction imaging. Hysteresis was
observed in ~50 % of tumors.
Shah et al. (2013a, b). Analysis of intrafraction varia-
tion in target position during lung tumor Linac-based
SBRT in 409 patients. Mean target position (MTP) was
calculated as the difference between the post setup-
shift verification CBCT and post-treatment
CBCT. MTP vector was 3.1 ± 2.0 mm, influenced by
weight and pulmonary function, and varied with dif-
ferential motion management techniques. PTV mar-
gins of ≥6 mm were recommended in the absence of
motion management interventions.
7. Lung 133
Bouihol et al. (2012). Study of abdominal compression

device in 27 early-stage NSCLC patients undergoing
lung SBRT. Results indicated significant reduction of
tumor amplitude for lower lobe lesions vs. mid/upper
lobe lesions (3.5 mm vs. 0.8 mm, p = 0.026), associated
with a mean ITV reduction of 3.6 cm3 vs. 0.2 cm3.
Xiao et al. (2009). Twenty treatment plans of 60 Gy in
3 fractions SBRT from RTOG 0236, generated without
heterogeneity corrections, were recalculated (but not
reoptimized) with heterogeneity corrections (superpo-
sition/convolution), and demonstrated an average
volume reduction of 10.1 ± 2.7 % from the original
95 % PTV receiving 60 Gy per protocol (p = 0.001). In
addition, the maximal point dose at ≥2 cm from the
PTV increased from 35.2 ± 1.7 to 38.5 ± 2.2 Gy.
Narabayashi et al. (2012). Review of 20 early-stage
NSCLC SBRT treatment plans comparing the effect
of different heterogeneity calculation methods on
dosimetric parameters. Use of Monte Carlo heteroge-
neity correction with D95 prescription results in
increase of 8.8 % and 16.1 % as compared to BPL and
RPL methods, respectively.
Follow-Up
Categorization and quantification of post-SBRT radio-

graphic changes for objective response criteria and
relationship between radiographic changes and tumor
response and toxicity is an active area of investigation.
Takeda et al. (2007). Review of post-treatment CXR
and CT for 50 patients treated with SBRT (50 Gy in 5
fractions) for early-stage peripheral NSCLC with
minimum 1-year follow-up. Twenty patients showed
opacities concerning for recurrence, with three patients
showing clear evidence clinical and/or pathological of
recurrence with a median follow-up of 21 months.
Dahele et al. (2011). Review of post-treatment CT
scans of 61 patients who received SBRT at VUMC for
early-stage NSCLC with no definitive evidence of recur-

rence. Median follow-up was 2.5 years. Radiologic
abnormalities noted in 54 % of scans at 6 months and
99 % at 36 months. Most common changes were acute
patchy consolidation (24 %) and late consolidation, vol-
ume loss, and bronchiectasis (71 %).
Trovo et al. (2010). Review of post-treatment CT scans
of 68 patients (largely SBRT-treated early-stage
NSCLC) from 6 weeks to 18 months. Early radio-
graphic changes included diffuse and patchy consoli-
dation and GGO, increased from 6 weeks (46 %) to 6
months (79 %). Late changes included consolidation,
volume loss, and bronchiectasis with mass- and scar-
like fibrosis in 88 % of scans at >12 months.
Diot et al. (2012). Review of CT scans of 62 patients
who received SBRT for early-stage primary NSCLC
and metastatic pulmonary lesions. CT numbers showed
a dose–response relationship to 20–35 Gy over the 3-
to 30-month period post-SBRT.
Bollneni et al. (2012). Review of 132 medically inoper-
able stage I NSCLC patients treated with 60 Gy in 3–8
fractions. Max SUV on PETCT at 12 weeks ≥5.0 was
associated with 2 years LC of 80 % vs. 98 % for max
SUV < 5.0 (p = 0.019).
Screening and Diagnosis
National Lung Screening Trial (NLST Team 2011,

2013). Phase III trial of 50 k individuals at high risk of
tobacco-related lung malignancy (55–74-year-old with
30+ pack-year smoking history) randomized to base-
line and two subsequent annual screening exams with
low-dose CT (1.5 mSV) vs. CXR (0.1 mSv). At median
follow-up of 6.5 years, there was 20 % reduction in
lung cancer mortality and 6.7 % reduction in all cause
mortality with low-dose CT screening. Sensitivity
>90 %, specificity ~75 %, PPV ~5 %, NPV ~100 %.
7. Lung 135
Rates of lung cancer detected within 3 years: Stage I

(63 %) vs. Stage IIIB/IV (21 %).
Prostate, Lung, Colon, Ovarian (PLCO) Screening
Trial (Hocking et al, 2010;Tammemagi et al. 2011).
Phase III trial of 154 k individuals randomized to 1:1
CXR screening (3 years of annual CXR) vs. no screen-
ing. Fifty-two percent were current or former smokers.
PPV all 2.4 % at 3 years, 5.6 % for current smokers.
Early-stage NSCLC was enriched in the screening arm
(~60 %) vs. interval arm (~33 %).
NELSON Study (van Klaveren et al. 2009, Ru Zhao
et al. 2011). Phase III randomized trial of 15 k heavy
smokers (current and ≤10 year former with 25–30
years use) randomized to interval CT screening (base-
line, 1 and 3 years thereafter). Second-round screening
had sensitivity of 96 %, specificity 99 %, PPV 42 %,
NPV 100 %. Of detected NSCLC, 64 % were stage I.
Newman et al. (2014). Application of CAPP-seq
method to detect presence of NSCLC via mutant
allele targeting in ctDNA within peripheral blood
specimens. Method was validated in biopsy-proven
and screening settings with ctDNA detection rates of
100 % in stage II-IV patients and 50 % in stage I.
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Chapter 8
Digestive System
David R. Raleigh and Albert J. Chang
Pearls
Although surgery is the primary treatment modality
for pancreatic cancer, as well as oligometastases to the
liver, abdominal lymph nodes, and adrenal glands,
SBRT is feasible and well tolerated and may achieve
high rates of LC.
Response criteria following SBRT for digestive system
malignancies may include radiographic characteristics,
serum tumor markers (CA 19-9, CEA, etc.), and/or
clinical findings.
Toxicity is increased after SBRT in patients who have
previously been irradiated.
Numerous SBRT dose/fractionation schemes have
been investigated; lower doses and higher fraction-
ation may be more appropriate for lesions located
near/within critical structures such as the liver hilum,
or in patients with poor performance status.
D.R. Raleigh • A.J. Chang ()

e-mail: changAJ@radonc.ucsf.edu

146 D.R. Raleigh and A.J. Chang
Workup
H&P
Pancreas cancer: alcohol use, tobacco use, obesity,
BRCA, Peutz-Jeghers syndrome, Familial atypical
Multiple-Mole Melanoma syndrome, Ataxia
Telangiectasia.
Hepatocellular carcinoma: Hepatitis B, Hepatitis C,
Hereditary Hemochromatosis, alcohol use, afla-
toxin exposure, betel nut chewing, nonalcoholic
fatty liver disease.
Review of systems: Weight loss, epigastric pain,
jaundice.
Laboratories
General: CBC, LFTs, LDH, chemistries, and coagu-
lation panel.
Liver: Serum AFP, Total bilirubin, albumin, INR,
Hepatitis B/C panels, and multiphasic liver CT +/−
hepatic protocol MRI. Calculate Childs-Pugh score
to estimate liver function. Use increased caution in
patients with Childs-Pugh B and C.
Pancreas: Serum CA 19-9, CEA, amylase, lipase.
Imaging
CT abdomen with contrast; individualization of
additional imaging studies depending on suspected
tumor location (i.e., ERCP/MRCP/EUS for pancre-
atic and biliary malignancies, triphasic CT and/or
MRI for hepatic malignancies, etc.).
Pathology
If histology is unknown, CT-guided biopsy for
hepatic, adrenal and nodal metastases.
Endoscopic retrograde cholangiopancreatography
with stent placement and/or endoscopic ultrasound
(EUS) guided biopsy is preferred for pancreatic
masses, although laparoscopic staging and
CT-guided biopsy are also feasible.
8. Digestive System 147
Treatment Recommendations
Disease site Presentation Recommended treatment
Pancreas Resectable Surgery +/− adjuvant
chemoradiotherapy or
chemotherapy
Borderline Neoadjuvant chemoradiation
resectable followed by restaging and
(adequate KPS) resection if feasible
Borderline Definitive chemoradiation,
resectable conventionally fractionated
(poor KPS) radiation alone, chemotherapy
unresectable alone, or SBRT
Metastatic Palliation with stents, surgical
bypass, chemotherapy, RT, and
supportive care as indicated;
SBRT not indicated except
for expedient palliation
Liver Resectable Partial hepatectomy
HCC or
oligometastatic
disease with
controlled
primary
Unresectable/ Upfront Liver transplant
medically Restaging and resection if
inoperable feasible following transarterial
HCC or chemoembolization,
oligometastatic radiofrequency ablation,
disease with cryotherapy, alcohol, SBRT,
controlled or sorafenib
primary
Abdominal, Metastatic Systemic therapy preferred,
retroperitoneal, disease although surgery and SBRT
and pelvic should be discussed in
lymph nodes oligometastatic settings or for
palliation of pain
Adrenal Metastatic Systemic therapy preferred,
glands disease although surgery and SBRT
should be discussed in
oligometastatic settings or for
palliation of pain
Simulation and Field Design
Gold seed marker (GSM) placement by EUS

(pancreas) or CT-guidance (liver) 1+ week prior to
simulation to allow inflammation to subside.
Oral contrast 30–60 min prior to simulation, unless
MRI used for planning.
Supine with arms above head and wingboard or alpha
cradle to stabilize torso. Consider abdominal compres-
sion depending on image guidance modality.
Pancreas lies at L1-L2, celiac axis at T12, and SMA at L1.
Treatment planning:
Contrast-enhanced CT and/or MRI useful for delin-
eating pancreatic tumor volume; triphasic CT and/
or MRI for hepatic malignancies.
Image guidance:
Preferred: 4D-CT to define ITV with daily on-
board imaging for set-up and tracking.
Acceptable: Active breathing control (ABC),
orthogonal MV imaging and kV fluoroscopy.
Field Design: ITV based on 4D-CT plus 3–5 mm margin.
Optimal: ITV based on 4D-CT plus 3–5 mm margin
for PTV.
Other tracking/immobilization strategies typically
require 5–7 mm radial and 1–1.5 cm craniocaudal
expansions on GTV for adequate coverage.
Caution regarding inclusion of edema surround-
ing pancreatic tumors due to excessively large field
size.
Consider reducing PTV to allow for 2 mm margin to
critical structures, especially in patients with poor
performance status who are unlikely to tolerate
exploratory laparotomy for bleeding, perforation, etc.
Avoid or minimize elective nodal stations in SBRT
field due to toxicity.
Dose Prescription
Pancreas: 33 Gy in 5 fractions.
Liver: Based on location and underlying liver function.
Peripheral: 23–30 Gy in 1 fraction, 27.5–60 Gy in
3–6 fractions.
Central: 40 Gy in 5 fractions.
Abdominal lymph nodes based on retrospective case
series: 45–60 Gy in 3–6 fractions.
Adrenal metastases based on retrospective case
series: 23 Gy in 1 fraction, 36 Gy in 3–5 fractions
(Figs. 8.1 and 8.2).
Fig. 8.1. Pancreatic SBRT. 88-year-old male with locally advanced,

unresectable pancreatic adenocarcinoma. A 4D CTV with an ITV
expansion was used for treatment planning, which was carried out via
robotic radiosurgery to a total dose of 3000 cGy in 5 fractions with 6
MV photons prescribed to the 73 % isodose line. Proceeding clock-
wise from the top left, beam angles, and axial, coronal, and sagittal CT
images with isodose lines and the PTV in red color wash are shown
Fig. 8.2. Liver SBRT. 61-year-old male with a history of hepatitis C

and recurrent hepatocellular carcinoma of the porta hepatis status
post transcatheter arterial chemoembolization on four occasions,
and alcohol injection twice. A single intra-lesional fiducial marker
was used for tracking during robotic radiosurgery. The tumor was
treated to a total dose of 4000 cGy in 5 fractions with 6 MV photons
prescribed to the 82 % isodose line. Proceeding clockwise from the
top left, beam angles, and axial, coronal, and sagittal CT images with
isodose lines and the PTV in red color wash are shown
Dose Limitations
Dose
limiting
Structure Fractions Constraints toxicity Study
Stomach 1 V22.5 Gy < 4 % Ulceration, Chang
Distal lumen fistula et al.
wall free from Cancer
50 % isodose 2009
line
3 Dmax < 30 Gy Kavanagh
et al.
IJROBP
2010
6 Dmax < 32 Gy Bujold
D3 cc < 36 Gy et al. JCO
2013, Tozzi
et al. Rad
Onc 2013
Small 1 V12.5 Gy < 30 cc Ulceration, Kavanagh
bowel fistula et al.
IJROBP
2010
et al. JCO
2013
6 Dmax < 36 Gy Kavanagh
et al.
IJROBP
2010
Duodenum 1 V22.5% < 5 % Ulceration, Chang
V12.5 Gy < 50 % fistula et al.
Distal lumen Cancer
wall free from 2009
50 % isodose
line
D1 cc < 36 Gy et al. JCO
2013, Tozzi
et al. Rad
Onc 2013
(continued)
(continued)
Dose
limiting
Large 6 Dmax < 36 Gy Colitis, Bujold
bowel fistula et al. JCO
2013
Liver 1 V5 Gy < 50 % Liver Chang
V2.5 Gy < 70 % function, et al.
cirrhosis/ Cancer
hepatitis, 2009
1, 3-5 700 cc < 15 Gy biliary Rusthoven
stricture, et al. JCO
radiation- 2009,
induced Pan et al.
liver disease IJROBP
(RILD) 2010,
Goodman
et al.
IJROBP
2010
3-6 HCC: Pan et al.
MNLD < 13 Gy IJROBP
(3 fx), <18 Gy 2010
(6 fx)
Metastases:
MNLD < 15 Gy
(3 fx), < 20 Gy
(6 fx)
5 V30 Gy < 60 % Katz et al.
V27 Gy < 70 % IJROBP
for cirrhosis/ 2007
hepatitis
6 Vtot– Tozzi et al.
V21 Gy > 700 cc Rad Onc
2013
(continued)
(continued)
Dose
limiting
Kidney 1 V5 Gy < 75 % Kidney Goodman
function, et al.
malignant IJROBP
hypertension 2010
6 V15 Gy < 35 % Rusthoven
Mean et al. JCO
dose < 12 Gy 2009, Tozzi
et al. Rad
Onc 2013,
Bujold
et al. JCO
2013
Spinal cord 1 Dmax < 12 Gy Myelitis Goodman
et al.
IJROBP
2010
6 Dmax < 18 Gy Rusthoven
et al. JCO
2009, Tozzi
et al. Rad
Onc 2013
Chest wall 3 V30 Gy < 10 mL Pain or Rusthoven
fracture et al. JCO
2009
6 Dmax < 54 Gy Dawson
et al. Acta
Oncol 2006
Heart 6 Dmax < 40 Gy Pericarditis Dawson
et al. Acta
Oncol 2006

Acute complications such as nausea and vomiting can
occur immediately or within hours of treatment, and
may be effectively managed or even prophylaxed with
oral medications.
Inflammation after GSM placement for tracking of
pancreatic/hepatic tumors may lead to biliary sys-
tem stenosis requiring (re)stenting.
Long-term complications:
Dyspepsia, cramping, and diarrhea from mucosal
injury or ulceration, potentially leading to weight
loss from malabsorption, as well as fistulae, bleed-
ing, and perforation; difficult to manage beyond
best supportive care.
Bowel wall fibrosis leading to adhesions and
obstruction, potentially requiring laparoscopy/
laparotomy for resolution.
Chest wall pain and rib fractures, especially with
hepatic SBRT.
Pancreatic and adrenal insufficiency potentially
requiring exogenous supplementation.
Radiation-induced liver damage (RILD) typically
occurs within 3 months of therapy, and may lead to
hepatic failure and death; treatment options are
limited to supportive measures.
Classic RILD is associated with anicteric hepa-
tomegaly, ascites, and alkaline phosphatase ele-
vation due to occlusion and obliteration of the
central veins with secondary hepatocyte
necrosis.
Nonclassic RILD is associated with transaminitis
greater than 5 times the upper limit of normal, or
worsening of Child-Pugh score by 2 or more in
the absence of classic features.
H&P, laboratories, and abdominal CT (multiphasic vs.
pancreatic protocol) every 3 months for 2 years, then
every 6 months thereafter to evaluate for disease
recurrence/progression.
Evidence
Pancreas
SBRT Boost Following Conventionally

Fractionated Chemoradiation
Stanford (Koong et al. 2005): Phase II study of 16

patients with unresectable pancreatic cancer treated
with 45 Gy IMRT in 25 fractions plus concurrent 5FU
or capecitabine, followed by SBRT boost to 25 Gy in 1
fraction within 1 month of CRT. Median OS 33 weeks,
with estimated 6-month survival 80 % and 1-year
survival of 15 %; 94 % FFLP (i.e., no evidence of
tumor growth within the treatment field) until death.
Two incidents of grade 3 toxicity; no grade 4+ events.
Treatment strategy abandoned in favor of intensive
systemic therapy followed by SBRT boost due to high
GI toxicity and necessary recovery period with
CRT → SBRT regimen.
Primary SBRT
Italy (Tozzi et al. 2013): Prospective analysis of 30

patients with unresectable (70 %) or recurrent (30 %)
pancreatic cancer treated with gemcitabine followed
by SBRT to 45 Gy in 6 fractions (reduced to 36 Gy in
6 fractions to meet constraints in 5 patients). CTV
defined as gross disease on arterial-phase CT, and
expanded 0.5 cm radially and 1 cm craniocaudally with
cropping to achieve 2 mm margin to critical organs for

PTV. Median follow-up 11 months. FFLP 85 % (96 %
for 45 Gy group); median PFS 8 months. OS 47 % at 1
year; median OS 11 months. No grade 3+ toxicity.
Stanford (Chang et al. 2009): Retrospective analysis of
77 pancreatic cancer patients ineligible for surgery
(58 % locally advanced, 14 % medically unfit, 19 %
metastatic, and 8 % recurrent) with primary tumors
<7.5 cm in diameter. Median follow-up 6 months (12
months in survivors). All received 25 Gy SBRT in 1
fraction with gemcitabine-based chemotherapy in 96 %.
6- and 12-month LC (91 % and 84 %), PFS (26 % and
9 %), and OS (56 % and 21 %) reported. 8 of 9 patients
who failed regionally (12 %) also failed distantly. 16 %
of patients previously received IMRT, including 3 out of
10 patients who had late grade 3+ toxicity.
Denmark (Hoyer et al. 2005): Phase II study of 22
patients with unresectable pancreatic cancer treated
with SBRT to Dmax 45 Gy in 3 fractions. GTV included
both tumor and surrounding edema; PTV defined as
CTV plus 0.5 cm transverse and 1 cm longitudinal
margins. Median OS 6 months; 1-year OS 5 %. 27 %
LF but only 5 % without concurrent regional/distant
failure. 66 % improvement in performance status, nau-
sea, pain, and analgesic requirement at 3 months. 22 %
of patients experienced severe acute GI toxicity within
14 days of treatment, including mucositis, ulceration,
and perforation. Poor outcome and likely due to low
BED, but with unacceptable toxicity due to large treat-
ment volume.
Ongoing
Pancreatic Cancer Radiotherapy Study Group (Stanford):

Presently accruing phase III trial of FOLFIRINOX
+/− SBRT in locally advanced pancreatic cancer
patients. Primary endpoint PFS; secondary endpoints
MFS, OS, LPFS, toxicity, FDG-PET response, and
QOL. Estimated primary completion 2018.
Liver
Technique
Stanford (Goodman et al. 2010): Phase I dose escala-

tion trial of single-fraction SBRT with motion tracking
of 3–5 implanted fiducial markers in 26 patients with
40 hepatic lesions. All lesions ≤5 cm and treated with
18–30 Gy SBRT in 4 Gy increments. 4D-CT used to
delineate ITV, which was then expanded 3–5 mm to
create a PTV. Median follow-up 17 months; no grade
2+ toxicity. LC 77 %, 2-year actuarial survival 50 %,
and median survival 28.6 months.
Princess Margaret Hospital (Dawson et al. 2006): Phase
I/II dose escalation trial including 79 patients (45 pri-
mary hepatic tumors, 34 metastases) to establish
immobilization scheme, radiation planning, PTV mar-
gin, image guidance, and prescription dose for liver
SBRT. GTV defined on exhale breath-hold triphasic
CT and/or MRI; 8 mm margin added for CTV, and
PTV margin individualized ≥5 mm based on extent of
liver motion. Target motion largest in the craniocaudal
dimension (average 29 mm), followed by anterior-
posterior (average 9 mm) and lateral (average 8 mm)
translocation. Active breathing control and image
guidance strategies (orthogonal MV imaging, orthogo-
nal kV fluoroscopy, and kV cone beam CT) resulted in
excellent intra-fraction reproducibility (median dis-
placement 1.5 mm), although inter-fraction errors
were larger (median displacement 3.4 mm). Dose
individualized to maintain 5–20 % risk of RILD;
median 36.6 Gy in 6 fractions (range 24–57 Gy).
Germany (Herfarth et al. 2000): Phase I/II study of 24
patients with hepatic metastases treated with single-
fraction SBRT; set-up accuracy evaluated under fluo-
roscopy using abdominal compression. Mean
displacements: lateral 1.8 mm, craniocaudal <5 mm,
and anterior-posterior 2 mm; diaphragm 7 mm.
Concluded high-accuracy set-up of body and target
can be achieved with abdominal compression alone.
Dose Response
Germany (Wulf et al. 2006): Prospective trial of “low

dose” (10 Gy × 3 or 7 Gy × 4) vs. “high dose” (12–
12.5 Gy × 3 or 26 Gy × 1) in 44 patients with 56 hepatic
lesions (5 primary liver cancer, 51 metastases). With
median follow-up of 15 months, borderline significant
correlation (p = 0.077) between dose and LC at 1 year
(86 % vs. 100 %) and 2 years (58 % vs. 82 %) in favor
of the “high dose” cohort that became significant for
predicting local control on multivariate analysis
(p = 0.0089). OS at 1 and 2 years was 72 % and 32 %,
respectively. No severe acute or late physician-reported
toxicity.
Metastases
Colorado (Rusthoven et al. 2009): Phase I/II trial of

SBRT in 47 patients with 1–3 hepatic metastases
<6 cm; median follow-up 16 months. Dose escalation
in Phase I from 36 to 60 Gy in 3 fractions; phase II dose
of 60 Gy in 3 fractions prescribed to the 80–90 % IDL.
GTV expanded 5 mm radially and 10 mm craniocau-
dally when using active breathing control, and 7 mm
radially and 15 mm craniocaudally when using abdom-
inal compression. LC at 1 and 2 years 95 % and 92 %,
respectively, with 100 % control of lesions <3 cm.
Median and 2-year overall survival 20.5 months and
30 %, respectively. One incident of grade 3 toxicity; no
hematologic complications in patients who later went
on to receive bevacizumab.
Rochester (Katz et al. 2007): Retrospective single-
institution experience with hypofractionated RT for
hepatic metastases. 69 patients with 174 hepatic lesions
(median size 2.7 cm) and >1000 mL normal liver.
Median SBRT dose 48 Gy in 2–6 Gy fractions pre-
scribed to the 80 % IDL (50 Gy in 5 fractions over 2
weeks preferred). PTV = GTV + 7 mm radial and
10 mm craniocaudal margins; respiratory gating used
during treatment. With median follow-up of

14.5 months, 20-month LC 57 %, 12-month PFS 24 %,
and median OS 14 months; no grade 3+ toxicity. 75 %
of initially treated patients developed additional
hepatic lesions, 93 % of which were amenable to
repeat SBRT.
Hepatocellular Carcinoma (HCC)
Princess Margaret Hospital (Bujold et al. 2013):

Sequential phase I (50 patients) and phase II (52
patients) trials of 24–54 Gy SBRT in 6 fractions. All
patients had Child-Turcotte-Pugh class A disease,
with at least 700 mL of non-malignant liver and ≤5
lesions, although 52 % received prior therapies, 55 %
had tumor vascular thrombosis (TVT), 61 % had
multiple lesions, and mean tumor size was 7.2 cm.
Active breathing control and abdominal compres-
sion used to minimize tumor movement; GTV
expanded 5–8 mm to create CTV, which was
expanded ≥5 mm to create a PTV. 1-year LC 87 %
(11 % CR, 43 % PR, and 45 % SD); SBRT dose and
enrolment in phase II prognostic for LC on univari-
ate analysis. Mean OS 17 months with TVT and
enrolment in phase II significant for survival on mul-
tivariate analysis. Extrahepatic disease not predic-
tive likely due to severity of hepatic disease in
enrolled patients. Grade 3 toxicity seen in >30 % of
patients, including 7 cases of death possibly related
to treatment in patients with TVT.
Adjuvant Radiation After Hepatectomy
Sweden (Gunvén et al. 2003): Retrospective, single-

institution experience. Four sites of liver-only recur-
rence after primary hepatectomy treated with
frame-based SBRT (20 Gy × 2 or 15 Gy × 3). 100 %
local control after 13–101 months follow-up.
Imaging Follow-Up
Germany (Herfarth et al. 2003): 131 multiphasic CT

scans performed on 36 patients before and after sin-
gle-fraction SBRT (mean dose 22 Gy) for hepatic
tumors. At a median time of 1.8 months post-treatment,
74 % of scans revealed interval development of a
sharply demarcated hypodense area surrounding the
treated region that shrunk over time.
Ongoing
RTOG 11-12: Sorafenib vs. SBRT (27.5–50 Gy in 5

fractions) followed by sorafenib in patients with hepa-
tocellular carcinoma unsuitable or refractory to radio-
frequency ablation or transarterial chemoembolization
who are not candidates for liver transplantation.
Primary endpoint overall survival; target accrual 368.
Abdominal, Pelvic, and Retroperitoneal

Lymph Nodes
Korea (Bae et al. 2012): Retrospective, single-
institution review of 41 patients with 50 colorectal
cancer metastases (12 lung, 11 liver, and 18 abdomi-
nal lymph nodes) treated with 45–60 Gy SBRT in 3
fractions. For LNs, GTV expanded 2–4 mm in all
dimensions to create PTV. With median follow-up of
28 months, 3- and 5-year PFS, LC, and OS rates were
40 %, 64 %, and 60 %, and 40 %, 57 %, and 38 %,
respectively. Cumulative GTV and SBRT dose statis-
tically prognostic for LC. One grade 3 perforation
after pelvic LN SBRT, and one grade 3 obstruction
after para-aortic SBRT.
Italy (Bignardi et al. 2011): Retrospective, single-
institution review of 19 patients with unresectable
abdominal and retroperitoneal LN oligometastases
treated with SBRT to 45 Gy in six consecutive daily
fractions prescribed to the 80 % IDL. Dose reduced

10–20 % in 6 cases to meet normal tissue constraints,
and chemotherapy held starting 3 weeks before RT
until disease progression. PTV expansion of 3 mm radi-
ally and 6 mm craniocaudally. Median 12-month fol-
low-up. Actuarial FFLP rate 78 % and OS 93 % at both
12 and 24 months, with PFS 30 % and 20 %, respec-
tively. Number of metastases (solitary vs. nonsolitary)
significant for PFS. No RT-associated grade 2+ events.
Adrenal Gland Metastases
Florence (Casamassima et al. 2012): Retrospective,

single-institution analysis of 40 patients with solitary
adrenal metastases treated with 36 Gy SBRT in 3 frac-
tions prescribed to the 70 % IDL, plus 8 patients treated
with 23 Gy SBRT in 1 fraction; median follow-up
16.2 months. 4D-CT used to create an ITV, which was
uniformly expanded 3 mm to create a PTV; cone beam
CT used for image guidance. Actuarial 1- and 2-year LC
90 % with only 2 local failures (mean time 4.9 months),
although all 48 patients failed distantly with OS 39.7 %.
One case of grade 2 adrenal insufficiency.
Arnaud et al. 2011: Retrospective matched pair series
of laparoscopic adrenalectomy vs. SBRT (36 Gy in 5
fractions prescribed to the 80 % IDL) for isolated
adrenal oligometastases in 62 patients with controlled
primary tumors. Mean follow-up 18 months. No dif-
ference in OS at 6 and 12 months between SBRT
(77 % and 62 %, respectively) and surgery (87 % and
77 %, respectively).
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Chapter 9
Genitourinary Sites
Michael Wahl, Albert J. Chang, Alexander R. Gottschalk,
and Mack Roach, III
Pearls
Prostate adenocarcinoma is considered to have low
α[alpha]/β[beta] ratio of approximately 1.5–3, making
it conducive to hypofractionated treatment.
Renal cell carcinoma α[alpha]/β[beta] ratio relatively
low (3–6).
Few studies on SBRT for bladder, renal, or other GU
sites.
Most prostate studies done using CyberKnife, but
standard linear accelerator-based SBRT acceptable.
Prostate SBRT more cost-effective and convenient for
patients than IMRT (Sher et al 2012).
No randomized trials assessing efficacy of SBRT com-
pared to standard treatments.
M. Wahl, MD () • A.J. Chang, MD, PhD •

A.R. Gottschalk, MD, PhD
M. Roach, III, MD
Department of Radiation Oncology and Urology,
University of California San Francisco, 1600 Divisadero Street,
Suite H1031, San Francisco, CA, USA

166 M. Wahl et al.
Disease
site Presentation Recommended treatment
Prostate Low risk Active surveillance,
RP, or definitive
radiation (IMRT with
IGRT, brachytherapy
monotherapy, or SBRT
monotherapy)
Intermediate risk RP or definitive radiation
(IMRT with prostate-
specific boost using
external beam radiation,
brachytherapy, or SBRT
boost), with short-
term ADT (4 months).
Consider HDR or SBRT
monotherapy in select
favorable patients
High risk RP or definitive radiation
(IMRT with prostate-
specific boost using
external beam radiation,
brachytherapy, or SBRT
boost), with long-term
ADT (2–3 years)
Residual disease RP, salvage HDR, or
after RT SBRT
Bladder Muscle invasive +/− neoadj
disease (T2-T4), chemo → radical
bladder preservation cystectomy or concurrent
candidate chemo-RT with
IMRT to bladder and
pelvis; consider SBRT
boost to tumor bed
(investigational)
Renal cell Unilateral disease, Nephrectomy +/− post-op
carcinoma medically operable RT
Unilateral disease, SBRT to primary lesion
medically inoperable
Bilateral or SBRT to lesion in
recurrent unresected kidney
contralateral disease
9. Genitourinary Sites 167
Work-Up
Prostate
Work-up performed per standard-of-care depending

on risk group.
H&P, focusing on urinary symptoms, erectile function,
bone pain, and DRE.
Labs: PSA, Testosterone, and LFTs for intermediate-
and high-risk patients anticipating androgen
deprivation.
TRUS-guided biopsy with >8 cores, with prostate vol-
ume measurement.
Bone scan or NaF PET/CT for any of the following
(per NCCN 2014):
PSA > 20.
T2 and PSA > 10.
GS > 7.
T3 or T4.
Symptoms.
Pelvic CT or MRI for T3, T4 or a probability of lymph
node involvement >10 % (per NCCN 2014).
Prostate MRI for treatment planning.
Bladder
H&P, labs: CBC, BUN, CR, Alk Phos, UA, Urine

cytology.
Cystoscopy with EUA.
Upper urinary tract imaging (IVP, CT urography, renal
U/S, ureteroscopy, or MRI urogram).
If muscle invasive, Chest XR or CT, Abdominal/pelvic
CT.
TURBT with random bladder biopsies, including pros-
tatic urethra if trigone involved.
168 M. Wahl et al.
Renal Cell Carcinoma
H&P (hematuria, flank pain, flank mass most common

presenting symptoms).
Labs: CBC, LFTs, BUN, Cr, LDH, UA.
CT abdomen, or MRI abdomen if concern for IVC
involvement.
CXR or CT Chest.
Bone scan, brain MRI only if clinically indicated.
Simulation and Field Design
Prostate
TRUS-guided placement of at least 3 gold seed mark-

ers (2 at base, 1 at apex) at least 1 week prior to
simulation.
Simulation: Enema day of simulation, full bladder,
supine with alpha cradle.
Fuse prostate MRI with simulation CT.
Consider enema 2–3 h prior to each treatment (per
RTOG 0938).
Image Guidance
CyberKnife:
Real-time fiducial tracking using orthogonal kV
x-ray fluoroscopy for intrafraction motion
(preferred).
Linac:
Daily image guidance using fiducials via EPID,
conebeam CT or helical tomo CT imaging.
If treatment time >7 min, repeat IGRT procedure
during treatment at least every 7 min.
Repeat IGRT procedure at end of treatment to
document stability during treatment.
Fig. 9.1 (b) Axial, (c) sagittal, and (d) coronal views of an example
prostate SBRT plan. Patient with low risk, cT1c, Gleason 6 prostate
cancer with PSA of 3.8 treated with SBRT monotherapy to 38 Gy in
4 fractions. Target volume is shown (shaded red), along with urethral
avoidance structure (blue). Prescription isodose line is shown in
orange, and 120 % of the prescription dose is shown in red. A typical
plan uses many (>100) non-coplanar, non-isocentric beams, as
shown in (a)
Treatment planning:
GTV: any lesion visible on MRI and/or based on
biopsy information.
CTV: prostate +/− proximal Seminal Vesicles on
CT/MRI fusion.
PTV: CTV + 3–5 mm expansion, sparing rectum.
Contour urethra as avoidance structure.
170 M. Wahl et al.
Fig. 9.2 Intrafraction fiducial tracking used for CK prostate treat-

ments. The three gold fiducial markers placed in the prostate are
visualized on orthogonal DRRs generated from the planning CT
(left), and on the live kV X-ray images (middle). During treatment
delivery, beams are automatically re-targeted based on the registra-
tion of fiducials on the two images (right) to account for intrafrac-
tion motion (within specific translational and rotational bounds)
Bladder
Placement of 3–4 gold seed markers delineating tumor

bed during TUBRT.
Simulation: Supine with alpha cradle. Full vs. empty
bladder controversial: less bowel toxicity with full
bladder; more setup reproducibility with empty blad-
der. At UCSF, we simulate with full bladder.
Image Guidance
CyberKnife: Real-time fiducial tracking for
intrafraction motion (preferred).
Linac: Daily image guidance with fiducials, with
EPID, CBCT, or helical tomo CT.
Treatment planning:
GTV: Macroscopic tumor visible on
CT/MRI/Cystoscopy.
CTVboost: GTV + 0.5 cm + tumor bed as delineated

by gold seed markers.
PTV = CTV + 1.5 cm.
Simulation: Supine with alpha cradle, arms above

head.
Obtain 4D-CT to define ITV.
Image guidance:
CyberKnife: Real-time fiducial tracking
Daily conebeam CT.
Field design
GTV: Tumor visible on planning CT.
ITV: Integrated tumor volume based on movement
on 4D-CT.
PTV: ITV + 3–5 mm.
Contour surrounding normal kidney as avoidance
structure.
Dose Prescriptions
Prostate SBRT monotherapy

Acceptable regimens: 7.25 Gy × 5 (most common),
9.5 Gy × 4.
QOD treatment given increased toxicity with daily
fractionation.
Consider simultaneous integrated boost to GTV if
dominant lesion visible on MRI.
Prostate SBRT boost
Acceptable regimens: 9.5 Gy × 2, 7 Gy × 3. At UCSF
we use 9.5 Gy × 2.
Prostate post-RT salvage
6 Gy × 5.
If focal recurrence demonstrated on biopsy and/or
MRI, consider partial volume treatment to domi-
nant intraprostatic lesion.
172 M. Wahl et al.
Bladder SBRT boost

3.5 Gy × 5 (equivalent to 20 Gy boost in 2 Gy frac-
tions assuming α[alpha]/β[beta] = 10).
Renal cell carcinoma
10 Gy × 4 (or 10 Gy × 3 if large).
Dose Limitations
Structure Fractions Constraints Source

Rectum 4 V75% < 2 cc UCSF (Jabbari et al 2012)
5 Dmax < 105 % RTOG 0938
Urethra 4 V120% < 10 % UCSF (Jabbari et al 2012)
5 Dmax < 107 % RTOG 0938
Bladder 4 V75% < 3 cc UCSF (Jabbari et al 2012)
5 Dmax < 105 % RTOG 0938
Penile 5 V54% < 3 cc RTOG 0938
bulb Dmax < 100 %
Femoral 5 V54% < 10 cc RTOG 0938
heads Dmax < 30 Gy
Renal 5 V17.5 < 200 cc TG101 (Benedict et al
cortex 2010)
Renal 5 V23 < 66 % TG101 (Benedict et al
hilum 2010)

Complications
Minimal toxicity data for bladder or renal SBRT.
Prostate
Acute:
GU (~50 %): Most commonly urinary frequency,
urgency.
Management: Tamsulosin, consider routine pre-

scription for 6 weeks after SBRT, longer as needed
for symptoms.
GI (30–40 %): Proctitis, Diarrhea
Management: Low residue diet, anti-diarrheals, rec-
tal amifostine have been shown to reduce symp-
toms (Simone et al 2008).
Long term:
Cystitis, urethral stricture, rectal ulcer (<10 %).
Erectile dysfunction (20–25 % rate with SBRT,
Chen et al 2013, Katz et al 2013).
Increased risk of urethral stricture if prior TURP;
contraindication to SBRT.
Prostate
H&P with DRE and PSA every 6 months for 5 years,

then annually thereafter. DRE may be omitted if
undetectable PSA (per NCCN 2014 Guidelines).
PSA “bounce,” previously observed in brachytherapy
patients, common in SBRT (10–20 %). Median time to
bounce 3 years.
Phoenix Definition of PSA >2 ng/mL above PSA
nadir results in fewer false-positive biochemical fail-
ures due to benign PSA bounces.
Evidence
Prostate
Dosimetric Comparison to HDR
Fuller et al. (2008): Treated 10 patients with CyberKnife

SBRT and performed simulated treatment planning
for HDR on same patients. Similar prostate coverage
174 M. Wahl et al.
and rectal wall doses for SBRT and HDR; more homo-
geneity, lower urethral dose and lower bladder maxi-
mum point dose for SBRT.
SBRT Monotherapy
No randomized studies of SBRT vs. other modalities,

and no studies with long-term (>4 years) follow-up.
All studies use Phoenix definition of biochemical fail-
ure (PSA nadir +2 ng/dl) unless otherwise specified.
Wisconsin (Madsen et al. 2007): Phase I/II trial of 40
patients with low-risk (GS < 7, PSA < 10, ≤T2a) disease
treated with 33.5 Gy in 5 fractions on consecutive days.
Conventional linear accelerator with fiducial markers
for daily positioning. Median follow-up of 41 months,
only 1 acute grade 3 GU toxicity reported with no late
grade 3 GI or GU toxicities. 4-year biochemical free-
dom from relapse of 90 %.
Winthrop (Katz et al. 2010a, b, 2013): Prospective study
of 304 patients with low (69 %), intermediate (27 %)
and high-risk (4 %) disease treated with 35 Gy in 5
fractions (first 50 patients) and 36.25 in 5 fractions (all
subsequent patients) using daily treatment with
CyberKnife. Median follow-up 60 months. No acute
grade 3 toxicity; 4.3 % and 3.6 % acute grade 2 GU
and GI toxicity, respectively. 2 % late grade 3 GU tox-
icity; 5.8 % and 2.9 % late grade 2 GU and GI toxicity,
respectively. 5-year bPFS for low-, intermediate-, and
high-risk patients: 97 %, 90.7 %, and 74.1 %.
Stanford (King et al. 2009, 2012): Prospective Phase II
trial of 67 patients with low-risk disease treated with
36.25 Gy in 5 fractions using CyberKnife. First 22
patients received daily treatment, subsequent patients
received QOD treatment. 33-month median follow-up.
2 patients with late grade 3 GU toxicity, none with
grade 3 GI toxicity. Grade 1–2 toxicity significantly
worse with daily vs. QOD treatment (GU: 56 % vs.
17 %, GI: 44 % vs. 5 %). 4-year bPFS 94 %.
Boike et al (2011): Phase I dose escalation study. 45

patients with low- or favorable intermediate-risk dis-
ease. First 15 patients treated with 45 Gy in 5 fractions,
next 15 with 47.5 Gy in 5 fractions, final 15 with 50 Gy
in 5 fractions, with a short median follow-up of 30, 18,
and 12 months, respectively. Patients treated on tomo-
therapy or conventional linear accelerator with fidu-
cials. 2 % Grade 3 GI toxicity, 4 % Grade 3 GU
toxicity across all groups. No PSA failures.
McBride et al. (2012): Prospective multi-institutional
Phase I study of 45 patients with low-risk disease
treated with 37.5 Gy in 5 fractions (34 patients) or
36.25 Gy in 5 fractions (10 patients) based on institu-
tion choice with CyberKnife. Median follow-up of
44.5 months. 19 % acute and 17 % late grade 2 GU
toxicities; 7 % acute and 7 % late GI toxicities. One
late grade 3 GU toxicity (obstructing requiring TURP)
and GI toxicity (proctitis requiring laser ablation).
3-year bPFS was 97.7 % with one death from unre-
lated cause and no biochemical failures.
Netherlands (Aluwni et al. 2013): Prospective study of
50 low- (60 %) and intermediate-risk (40 %) patients
treated with 38 Gy in 4 fractions with CyberKnife.
Simultaneous integrated boost to dominant lesion on
MRI (if observed) to 44 Gy. Median follow-up of 23
months. Acute grade 2/3 GI toxicity 12 %/2 %, late
grade 2/3 GI toxicity 3 %/0 %. Acute grade 2/3 GU
toxicity 15 %/8 %, late grade 2/3 GU toxicity 10 %/6 %.
No PSA failures.
Toronto (Loblaw et al. 2013): Prospective phase I/II
study of 84 low-risk patients treated with 35 Gy in 5
fractions over 28 days using standard linear accelera-
tors using image guidance with EPID. 55 months
median follow-up. 0–1 % late GI and GU toxicity.
5-year biochemical control 98 %. Conclusion: prostate
SBRT feasible with conventional linear accelerators.
Georgetown (Chen et al. 2013): Retrospective analysis
of 100 patients (37 low risk, 55 intermediate, 8 high)
176 M. Wahl et al.
treated with 7 or 7.25 Gy × 5 fractions. 1 % grade 2 or

higher GI toxicity, 31 % grade 2 or higher GU toxicity.
2-year bPFS 99 %.
Pooled analysis (King et al. 2013a, b): Combined analy-
sis of all published phase 2 trials from 8 institutions,
including most studies listed above. 1100 patients total
(58 % low risk, 30 % intermediate, 11 % high) treated
with CyberKnife; most received 36.25 Gy in 5 fractions
(range 35–40 Gy). Median follow-up 36 months. 5-year
bPFS 94 % for all patients (95 %, 83 %, and 78 % for
low, intermediate, and high risk, respectively). PSA
nadir decreased with increasing dose, but bPFS not
dependent on dose.
SBRT Boost After Conventionally

Fractionated Radiation
Winthrop (Katz et al. 2010a, b): Retrospective analysis

of 73 patients (41 intermediate risk, 32 high risk)
treated with SBRT boost after EBRT to 45 Gy. All
patients treated with CyberKnife, with doses of
6 Gy × 3, 6.5 Gy × 3, or 7 Gy × 3. 33 month median fol-
low-up; 3-year bPFS of 89.5 % for intermediate-risk
and 77.7 % for high-risk patients, with only one local
failure. <10 % Grade 2 and above acute or late toxicity,
with comparable urinary toxicity and decreased rectal
toxicity compared to EBRT and HDR boost historical
series. Of note, all patients underwent rectal amifos-
tine prior to each treatment.
Barcelona (Miralbell et al. 2010): Dose escalation
study of 50 patients with nonmetastatic prostate can-
cer (low risk 10 %, intermediate 24 %, high 66 %)
treated with EBRT to 64 Gy, then boosted with 10, 12,
14, or 16 Gy in 2 fractions (29/50 patients got 16 Gy)
using IMRT with abdominal stereotactic markers.
Boost volume consisted of peripheral zone only, +/−
SV depending on patient. Median follow-up 63 months.
5-year bPFS 98 %, with toxicity comparable to that

seen in dose escalation studies.
UCSF (Jabbari et al. 2012): Retrospective analysis of
38 patients treated with SBRT, 18 of whom underwent
SBRT boost to 19 Gy in 2 fractions with CyberKnife
after conventional external beam radiation. 72 % of
boost patients high risk. 18.3 months median follow-
up. No early Grade 3 toxicity; 2 late Grade 3 GU
events. 100 % bPFS, PSA nadir of 0.10 comparable to
comparison group of 44 patients receiving HDR
brachytherapy boost.
Salvage SBRT After Conventionally

Fractionated Radiation
Milan (Bolzicco et al. 2013): Case series of 6 patients

with PSA failure after EBRT to 70–80 Gy, and cho-
line-PET showing no evidence of metastatic disease.
All treated with 30 Gy in 5 daily fractions. Median
follow-up of 11.3 months. No severe early or late toxic-
ity, but 4 of 6 experienced biochemical progression,
with 3 patients developing regional or metastatic
disease.
Toxicity
Pooled analysis (King et al. 2013a, b): 864 patients

from pooled analysis described above completed serial
questionnaires up to 6 years after treatment. Transient
decline in urinary and bowel quality of life within
3 months following SBRT, returning to baseline within
6 months. Decline in sexual function observed, appre-
ciated within 9 months of treatment and persisting
thereafter.
178 M. Wahl et al.
Bladder
Thariat et al. (2010): Case study of a single patient with

prior pelvic radiation for rectal cancer, with pT2N0M0
urothelial carcinoma status post TURBT, treated with
24 Gy in 4 Gy fractions to tumor bed. Tolerated well,
with NED at 2 years.
Sweden (Svedman et al. 2008): Case series of 7 patients

with RCC with previous nephrectomy with metastatic
disease in contralateral kidney. All underwent SBRT
to functioning kidney lesion of 10 Gy × 3 or 10 Gy × 4.
Local control in 6 of 7 patients, preserved renal func-
tion in 5 of 7 patients.
References
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I-K, et al. Stereotactic body radiotherapy with a focal boost to the
MRI-visible tumor as monotherapy for low- and intermediate-
risk prostate cancer: early results. Radiat Oncol. 2013;8:84.
doi:10.1186/1748-717X-8-84.
Benedict SH, Yenice KM, Followill D, Galvin JM, Hinson W, et al.
Stereotactic body radiation therapy: the report of AAPM Task
Group 101. Med Phys. 2010;37:4078–101.
Boike TPT, Lotan YY, Cho LCL, Brindle JJ, DeRose PP, et al. Phase
I dose-escalation study of stereotactic body radiation therapy for
low- and intermediate-risk prostate cancer. J Clin Oncol.
2011;29:2020–6. doi:10.1200/JCO.2010.31.4377.
Bolzicco G, Favretto MS, Satariano N, Scremin E, Tambone C, et al.
A single-center study of 100 consecutive patients with localized
prostate cancer treated with stereotactic body radiotherapy.
BMC Urol. 2013;13:49. doi:10.1186/1471-2490-13-49.
Chen LN, Suy S, Uhm S, Oermann EK, Ju AW, et al. Stereotactic
body radiation therapy (SBRT) for clinically localized prostate
cancer: the Georgetown University experience. Radiat Oncol.
2013;8:58. doi:10.1186/1748-717X-8-58.
Fuller DB, Naitoh J, Lee C, Hardy S, Jin H (2008) Virtual HDRSM

CyberKnife Treatment for Localized Prostatic Carcinoma:
Dosimetry Comparison With HDR Brachytherapy and Preliminary
Clinical Observations. International Journal of Radiation
Oncology*Biology*Physics 70: 1588–1597. doi:10.1016/j.ijrobp.
2007.11.067.
Hinnen KAK, Monninkhof EME, Battermann JJJ, van Roermund
JGHJ, Frank SJS, et al. Prostate specific antigen bounce is related
to overall survival in prostate brachytherapy. Int J Radiat Oncol
Biol Phys. 2012;82:883–8. doi:10.1016/j.ijrobp.2010.11.049.
Jabbari SS, Weinberg VKV, Kaprealian TT, Hsu I-CI, Ma LL, et al.
Stereotactic body radiotherapy as monotherapy or post-external
beam radiotherapy boost for prostate cancer: technique, early
toxicity, and PSA response. Int J Radiat Oncol Biol Phys.
2012;82:228–34. doi:10.1016/j.ijrobp.2010.10.026.
Katz AJ, Santoro M, Ashley R, Diblasio F, Witten M. Stereotactic
body radiotherapy for organ-confined prostate cancer. BMC
Urol. 2010a;10:1–1. doi:10.1186/1471-2490-10-1.
Katz AJ, Santoro M, Ashley R, Diblasio F, Witten M. Stereotactic
body radiotherapy as boost for organ-confined prostate cancer.
Technol Cancer Res Treat. 2010b;9:575–82.
Katz AJ, Santoro M, Diblasio F, Ashley R. Stereotactic body radio-
therapy for localized prostate cancer: disease control and quality
of life at 6 years. Radiat Oncol. 2013;8:118. doi:10.1186/1748-
717X-8-118.
King CR, Brooks JD, Gill H, Pawlicki T, Cotrutz C, et al. Stereotactic
Body Radiotherapy for Localized Prostate Cancer: Interim
Results of a Prospective Phase II Clinical Trial. Int J Radiat Oncol
Biol Phys. 2009;73:6–6. doi:10.1016/j.ijrobp.2008.05.059.
King CR, Brooks JD, Gill H, Presti JC Jr. (2012) Long-Term
Outcomes From a Prospective Trial of Stereotactic Body
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Biol Phys; 2013a. doi:10.1016/j.ijrobp.2013.08.019.
King CR, Freeman D, Kaplan I, Fuller D, Bolzicco G, et al.
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2013.03.022.
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clinical trial results. Int J Radiat Oncol Biol Phys. 2007;67:7–7.
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fractionation sensitivity of prostate cancer deduced from radio-
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Comparative cost-effectiveness of stereotactic body radiation
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for localized prostate cancer. Front Oncol. 2012;2:81. doi:10.3389/
fonc.2012.00081.
Sher DJ, Parikh R, Mays-Jackson S, Punglia RS (2012) Cost-
effectiveness Analysis of SBRT Versus IMRT for Low-risk
Prostate Cancer. American Journal of Clinical Oncology: –.
doi:10.1097/COC.0b013e31827a7d2a.
Simone NL, Ménard C, Soule BP, Albert PS, Guion P, et al. Intrarectal
amifostine during external beam radiation therapy for prostate
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measured by EPIC score. Int J Radiat Oncol Biol Phys.
2008;70:90–5. doi:10.1016/j.ijrobp.2007.05.057.
Svedman CC, Karlsson KK, Rutkowska EE, Sandström PP, Blomgren
HH, et al. Stereotactic body radiotherapy of primary and meta-
static renal lesions for patients with only one functioning kidney.
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Onkol. 1993;169:740–4.
Chapter 10
Gynecologic Sites
Zachary A. Seymour, Rajni A. Sethi, and I-Chow Joe Hsu
Pearls
SBRT has been employed in recurrent, oligometa-
static, and up-front settings for gynecologic tumors,
alone or with EBRT.
There are no randomized trials to evaluate the efficacy
and toxicity of SBRT in these settings.
Local control rate for SBRT re-irradiation of lymph
node or distant metastatic sites is ≥65 %. Local control
of small tumors approaches 100 % (Choi et al. 2009;
Deodato et al. 2009; Guckenberger et al. 2010).
Local control rate for SBRT re-irradiation for pelvic
sidewall failures is ~50 % (Dewas et al. 2011).
Distant metastasis is the most common failure pattern
after SBRT for recurrent tumors with 45–70 % 2–4-
year distant failure rate.
Z.A. Seymour • R.A. Sethi • I.-C. J. Hsu ()

San Francisco, 1600 Divisadero Street, Suite H1031, San Francisco,
CA 94143, USA
e-mail: ihsu@radonc.ucsf.edu

184 Z.A. Seymour et al.
While early studies have explored SBRT techniques to
administer a boost dose in definitive radiotherapy for
gynecologic malignancies, brachytherapy remains the
gold standard for this purpose.
SBRT should not be used for salvage of central recur-
rences within high-dose region of the prior treatment
field in patients who have undergone definitive radia-
tion due to high potential toxicity.
Presentation Treatment recommendations

Isolated lateral pelvic Resection, palliative EBRT,
recurrences SBRT,
or systemic therapy
Isolated nodal recurrence Resection, EBRT ± SBRT, SBRT
alone, or systemic therapy
Oligometastatic disease Resection, SBRT, or systemic
therapy
Work-Up and Recommended Imaging

H&P, including prior radiotherapy, detailed gyneco-
logic history, performance status, pelvic examination.
Review of systems.
Vaginal bleeding.
Pelvic or back pain.
Neuropathy associated with sidewall recurrences
leading to leg pain or weakness.
Bowel or bladder symptoms.
Labs.
CBC, metabolic panel, liver function tests.
Imaging.
MRI within 2 weeks of SBRT.
PET/CT or CT with contrast as alternatives for
recurrent disease.
Pathology.
FNA or CT-guided biopsy of accessible lesions.
10. Gynecologic Sites 185
Supine position, arms on chest or overhead.

Immobilization with body frame and/or fiducial or
spine tracking.
Thin-cut CT (≤2.5 mm thickness) recommended.
IV and oral contrast to delineate bowel and vessels.
GTV is contoured using fusion of the MRI or PET/CT
scan merged into the area of interest on simulation
CT scan.
PTV = GTV + 3–8 mm (dependent upon site-specific
motion considerations).
Low dose to organs at risk can be achieved using a
large number of beam angles and smaller margins.
Phantom-based QA on all treatment plans prior to
delivery of first fraction.
Dose Prescription
Doses are divided into 1–5 fractions usually over 1–2
weeks.
SBRT alone in previously un-irradiated sites:
6 Gy × 5 fractions (Deodato et al. 2009; Higginson
et al. 2011).
11–15 Gy × 3 fractions (Choi et al. 2009).
SBRT alone in previously irradiated fields:
8 Gy × 3 fractions (Kunos et al. 2012).
6 Gy × 5–6 fractions (Deodato et al. 2009; Dewas
et al. 2011).
5 Gy × 5 fractions (UCSF unpublished).
SBRT with EBRT 45 Gy for PALN recurrences:
5 Gy × 4–5 fractions (Higginson et al. 2011).
In series where SBRT has substituted for brachyther-
apy boost during initial treatment of the primary
tumor, dose prescriptions mimic commonly accepted
brachytherapy schedules.
Dose prescribed to 70–80 % IDL.
Dose Limitations
Dose limitations to normal structures should meet

accepted brachytherapy standards or those as outlined
in TG-101 (see Appendix).
In the setting of re-irradiation, composite planning
should be employed, with appropriate BED conver-
sion for dose summation.
Dose Delivery
Initial verification by kV X-ray or CBCT to visualize

the tumor or surrogate markers for positioning.
Verification imaging should be repeated at least every
5 min for longer treatments.

Grade 3 or higher acute toxicity or severe late toxicity
is rare.
Common acute toxicities:
Fatigue: Usually self-limiting but may last for sev-
eral weeks to months.
Urethritis/cystitis: Treatment with phenazopyridine
or topical analgesics at the urethra.
Dermatitis: Skin erythema, hyperpigmentation, dry
desquamation. Limited by increased number of
beam angles to reduce entrance and exit doses.
Treated with supportive care, including moisturiz-
ers, low-dose steroid creams, topical analgesics, and
antimicrobial salves.
Diarrhea/proctitis: Managed with low-residue diet
and antidiarrheals.
Nausea: More common with treatment of retroperi-
toneal nodes leading to bowel dose. Pretreatment
with antiemetic 1 h prior to each fraction can limit
acute episodes of nausea after treatment.
Moderate or severe late toxicities:

Vaginal stenosis: Managed with vaginal dilator
every other day.
Ureteral stricture: Expectant management or
dilatation.
Vesicovaginal or rectovaginal fistula: Surgical
management.
Intestinal obstruction: Managed with bowel rest or
surgical management.
Soft tissue necrosis has been observed particularly
in the re-treatment setting.
Pelvic exam every 3 months for 2 years, then every
6 months for 3 years, then annually.
For cervical cancers, Pap-smear every 6 months for 5
years then annually. Pap-smear surveillance should
start 6 months after treatment due to post-radiation
changes.
PET/CT or CT A/P with contrast 3 months after
completion of therapy.
Evidence
SBRT as Re-irradiation for Recurrent Tumors
Kunos et al. (2012): Prospective phase II study, 50

patients with primary gynecologic site, recurrence in
≤4 metastases. Treatment sites were PALN (38 %),
pelvis (28 %), other distant sites including abdomen,
liver, lung, bone (34 %). Dose was 8 Gy × 3 fractions to
70 % IDL with Cyberknife. CTV = PET-avid lesions.
PTV = CTV + 3 mm. Thirty-two percent had treatment
in previously irradiated field. Median follow-up for
surviving patients 15 months. No SBRT-treated lesion
progressed. Sixty-four percent recurred elsewhere.

Three patients (6 %) had grade 3–4 toxicity (one grade
3 diarrhea, one enterovaginal fistula, one grade 4
hyperbilirubinemia).
Dewas et al. (2011). Retrospective study of 16 previ-
ously irradiated patients (45 Gy median dose) with
pelvic sidewall recurrences. Primary tumors were cer-
vix (n = 4), endometrial (n = 1), bladder (n = 1), anal
(n = 6), rectal (n = 4). Treatment was 36 Gy to 80 %
IDL in 6 fractions over 3 weeks with Cyberknife.
Median maximum tumor diameter 3.5 cm. 10.6 month
median follow-up. One year actuarial LC 51 %. Median
DFS 8.3 months. Four of 8 patients with sciatic pain
had reduction in pain by end of treatment but none
were able to discontinue opiates. No grade 3 or higher
toxicity.
Choi et al. (2009): Retrospective study of 28 cervical
cancer patients with isolated PALN metastases.
Twenty-four had SBRT 33–45 Gy in 3 fractions; 4 had
EBRT followed by SBRT boost. PTV = GTV + 2 mm.
Rx to 73–87 % IDL. Twenty-five patients received
cisplatin-based chemotherapy before (n = 2), during
(n = 9) or after (n = 14) SBRT. Four years LC was 68 %
overall, 100 % if PTV volume ≤17 mL.
Higginson et al. (2011): Retrospective study of 16
patients treated with SBRT (9 recurrences, 5 SBRT
boost, 2 oligometastatic). SBRT doses were 12–54 Gy
in 3–5 fractions. Eleven patients had additional EBRT
30–54 Gy. Eleven months median follow-up. LC 79 %.
Distant failure 43 %.
Guckenberger et al. (2010): Retrospective study of 19
patients with isolated pelvic recurrence after primary
surgical treatment (12 cervix, 7 endometrial prima-
ries). 16 previously un-irradiated had 50 Gy EBRT
followed by SBRT boost; 3 patients with prior RT had
SBRT alone. Patients were selected for SBRT over
brachytherapy due to size (>4.5 cm) and/or peripheral
location. Dose for SBRT boost was 5 Gy × 3 fractions
to median 65 % IDL; SBRT only 10 Gy × 3 fractions or

7 Gy × 4 fractions to the 65 % IDL. Three years LC
81 %. Median time to systemic progression 16 months.
Sixteen percent severe complication rate (2 intestino-
vaginal fistulas and one small bowel ileus). Two of the
patients with severe complications had prior pelvic
RT ± brachytherapy and had bowel maximum point
dose of EQD2 >80 Gy.
Deodato et al. (2009): Retrospective study of 11
patients, dose escalation with 5 daily SBRT fractions
up to 6 Gy per fraction, in previously irradiated (n = 6)
or previously un-irradiated (n = 5) patients with recur-
rent gynecologic tumors. Two years local PFS 82 %.
Two years DMFS 54 %. No grade 3–4 toxicity.
SBRT Boost in Initial Definitive Radiotherapy
Kemmerer et al. (2013): Retrospective study of 11

patients with stage I–III endometrial cancer. Definitive
EBRT 45 Gy followed by SBRT boost to the high risk
CTV (1 cm around endometrium and any gross dis-
ease after EBRT). Dose: 30 Gy/5 fractions in nine
patients, 20–24 Gy/4 fractions in two patients, two frac-
tions/week. IMRT-based treatment with daily kV
CBCT. Ten-month median follow-up. One year FFP of
68 % for all patients, two years FFP 100 % for Grade
1 or stage IA tumors. Eighty percent of failures were
in endometrium. One grade 3 toxicity (diarrhea).
Molla et al. (2005): Retrospective study of 16 patients
with endometrial (n = 9) or cervical (n = 7) cancer
treated with SBRT boost, 7 Gy × 2 (post-op, n = 12) or
4 Gy × 5 (no surgery, n = 4), two SBRT fractions per
week. PTV = CTV + 6–10 mm. Median follow-up 12.6
months. Dynamic arc therapy or IMRT was used. Only
1 failure in a cervix cancer patient. One patient had
grade 3 rectal toxicity (persistent rectal bleeding); was
treated previously with pelvic RT with HDR boost.
References
Choi CW, Cho CK, Yoo SY, Kim MS, Yang KM, Yoo HJ, et al. Image-
guided stereotactic body radiation therapy in patients with iso-
lated para-aortic lymph node metastases from uterine cervical and
corpus cancer. Int J Radiat Oncol Biol Phys. 2009;74(1):147–53.
Deodato F, Macchia G, Grimaldi L, Ferrandina G, Lorusso D,
Salutari V, et al. Stereotactic radiotherapy in recurrent gyneco-
logical cancer: a case series. Oncol Rep. 2009;22(2):415–9.
Dewas S, Bibault JE, Mirabel X, Nickers P, Castelain B, Lacornerie T,
et al. Robotic image-guided reirradiation of lateral pelvic recur-
rences: preliminary results. Radiat Oncol. 2011;6:77.
Guckenberger M, Bachmann J, Wulf J, Mueller G, Krieger T, Baier K,
et al. Stereotactic body radiotherapy for local boost irradiation in
unfavourable locally recurrent gynaecological cancer. Radiother
Oncol. 2010;94(1):53–9.
Higginson DS, Morris DE, Jones EL, Clarke-Pearson D, Varia MA.
Stereotactic body radiotherapy (SBRT): technological innova-
tion and application in gynecologic oncology. Gynecol Oncol.
2011;120(3):404–12.
Kemmerer E, Hernandez E, Ferriss JS, Valakh V, Miyamoto C, Li S,
et al. Use of image-guided stereotactic body radiation therapy in
lieu of intracavitary brachytherapy for the treatment of inopera-
ble endometrial neoplasia. Int J Radiat Oncol Biol Phys. 2013;
85(1):129–35.
Kunos CA, Brindle J, Waggoner S, Zanotti K, Resnick K, Fusco N,
et al. Phase II clinical trial of robotic stereotactic body radiosur-
gery for metastatic gynecologic malignancies. Front Oncol.
2012;2:181.
Molla M, Escude L, Nouet P, Popowski Y, Hidalgo A, Rouzaud M,
et al. Fractionated stereotactic radiotherapy boost for gyneco-
logic tumors: an alternative to brachytherapy? Int J Radiat Oncol
Biol Phys. 2005;62(1):118–24.
Chapter 11
Soft Tissue Sarcoma
Steve E. Braunstein and Alexander R. Gottschalk
Pearls
~12,000 cases/year and ~4700 deaths/year in the USA.
Associated with genetic predisposition syndromes:
NF-1, Retinoblastoma, Gardner’s syndrome,
Li-Fraumeni syndrome.
Most commonly metastatic to lung (extremity prima-
ries) or liver (retroperitoneal primaries).
Limb salvage surgery combined with pre or post-
operative radiotherapy is current standard of care for
extremity STS with LC >90 %.
Several STS histologies have been associated with lower
[alpha]/[beta] ratio, suggesting effective response with
hypofractionation, and demonstrated in several studies
of EBRT and SRS of brain and spinal STS metastases.
Common adjuvant systemic therapy includes doxoru-
bicin and ifosfamide, as well as imatinib for c-kit GIST.
Metastatic STS is associated with poor MS <1 year, but
treatment of oligometastatic disease is associated with
improved survival.
S.E. Braunstein () • A.R. Gottschalk

1600 Divisadero Street, Suite H1031, San Francisco,
CA 94143, USA
e-mail: steve.braunstein@ucsf.edu

192 S.E. Braunstein and A.R. Gottschalk
Work-Up and Recommended Imaging

H&P, CBC, BUN/Cr, ESR, LDH, plain X-ray films of
primary.
CT/MRI for treatment planning and assessment of
peritumoral edema.
Biopsy for primary (incisional biopsy preferred).
Biopsy for suspected metastatic disease generally
avoided due to concern for further disease seeding.
Preoperative and/or postoperative EBRT and IORT
used in primary setting.
SBRT generally not recommended preoperatively due
to historically large margin recommendations for
extremity STS (3–5 cm longitudinal and 2 cm
circumferential).
Potential role for SBRT as small-volume postopera-
tive boost following preoperative EBRT and resection
with positive margins.
SBRT may be used in recurrent or metastatic disease,
primarily for symptomatic palliation. SBRT should be
strongly considered for patients with oligometastatic
disease who are poor surgical candidates due to
comorbidities or resectability concerns.

Extremity Early Surgery->EBRT for +/close
stage (I) margin
Intermediate- Surgery->post-op EBRT or
advanced pre-op EBRT->surgery, ±chemo
stage (II–III) for deep/high grade tumors
Retroperi- Resectable Surgery + IORT->post-op EBRT
toneal or pre-op EBRT->Surgery
+IORT
GIST Resectable Surgery ± imatinib
Unresectable Imatinib->re-eval±surgery
(continued)
11. Soft Tissue Sarcoma 193
(continued)
Desmoid Resectable Surgery±EBRT for +margin
Unresectable EBRT, chemo
Metastatic Chest, Surgical metastatectomy, SBRT,
(stage IV) abdominal, systemic therapy
or pelvic
oligometastases
Spinal Surgical resection/stabilization,
metastases EBRT/SBRT
Diffuse Systemic therapy, EBRT/SBRT
metastases for palliation of selected
involved sites
Dose and fractionation directed by adjacent normal
tissue RT toxicity constraints.

If biopsy or resection performed, request fiducial
marker placement.
Prefer fine-cut (<5 mm) treatment planning CT ± con-
trast with 4DCT to define ITV for thoracic or upper
abdominal metastases.
Immobilization with body frame and/or fiducial, lesion,
or vertebral element tracking.
Abdominal compression and/or respiratory gating
may be employed to reduce lesion motion associated
with diaphragmatic excursion during breathing.
Image fusion with diagnostic CT, MRI, myelogram,
and/or PET for target delineation as appropriate.
GTV/iGTV = lesion as defined by CT- or MRI-based
imaging, with contrast as available. Lung windowing
should be used for pulmonary oligometastases.
CTV/ITV = GTV/iGTV + 0–10 mm (CTV/ITV=GTV/
iGTV for pulmonary lesions).
PTV = CTV/ITV + 3–5 mm (smaller margins with

intrafraction image guidance and/or motion
management).
Image guidance with orthogonal kV and/or cone beam
CT for daily treatment delivery.
Dose Prescription
Central lung oligometastases.

10 Gy × 5 fx.
Peripheral lung oligometastases.
25–34 Gy × 1 fx, 18 Gy × 3 fx, 12 Gy × 4 fx, 10
Gy × 5 fx.
Abdominal and pelvic oligometastases.
6–8 Gy × 5 fx.
Vertebral spine metastases.
18–24 Gy × 1 fx, 8 Gy × 3 fx, 6 Gy × 5 fx.

EBRT late radiation morbidities include decreased
range of motion secondary to fibrosis at primary site,
lymphedema with circumferential treatment of
extremities, and low risk of secondary malignancy.
SBRT toxicity related to dose and volume of treated
adjacent normal tissues.
Risk of lung injury for pulmonary metastases (see
Chap. 7).
Risk of liver, adrenal, renal, and bowel toxicity for
abdominal metastases.
Nausea most common acute toxicity for abdominal
SBRT, often responsive to short-term antiemetic
pharmacotherapy.
Acute pain flare and risk of late myelopathy for spinal
metastases.
Exam with functional status, MRI of primary, CT chest
every 3 months × 2 years, then every 4 months × 1 year,
then every 6 months × 2 years.
CT imaging of treated oligometastatic site every
3 months × 1 year.
Consider bone scan, MRI, or PET, if clinically
indicated.
Evidence
There is lack of randomized prospective data on use
of SBRT approaches in primary, recurrent, and
metastatic disease.
Primary STS
While there is limited data regarding SBRT in man-

agement of primary STS, there is evidence of efficacy
of short-course adjuvant hypofractionated RT deliv-
ered via brachytherapy, as well as improved outcomes
with reduced treatment-volume IGRT and IMRT
techniques.
Itami et al. (2010): Retrospective series of 25 primary
STS patients treated postoperatively with HDR mono-
therapy, 36 Gy in 6 fx in 3 days b.i.d. LC 78.2 % at 5
years, but up to 93.3 % for patients with negative mar-
gins and no prior surgical resections. Complication
rate of 11.5 % >grade 2.
Petera et al. (2010): Retrospective series of 45 primary
or recurrent STS patients treated post-operatively
with HDR monotherapy (30–54 Gy, 3 Gy b.i.d fx) vs.
HDR (15–30 Gy, 3 Gy b.i.d. fx)+ EBRT (40–50 Gy at
1.8–2 Gy fx). LC 74 % and OS 70 % at 5 years. LC
better for primary tumors (100 %) and for patients
treated with combination HDR + EBRT vs. HDR
monotherapy (OR 0.2, p = 0.04).
Dickie et al. (2010) and Wang et al. (2011): Two phase II

studies of increased conformity of treatment volumes
employing image-guided preoperative IMRT suggest
improved rates of wound complications and late mor-
bidities including fibrosis, joint stiffness, and edema.
Alektiar et al. (2008). Retrospective series of 41 STS
patients treated with IMRT in pre- and postoperative
setting with increased bone sparing as compared with
prior 3DCRT techniques. Favorable 5-year LC of 94 %.
Soyfer et al. (2013): Series of 21 elderly patients with
median age 80 underwent post-operative hypofrac-
tionated EBRT 39–48 Gy in 13–16 fx. LC 86 % at
median follow-up of 26 months. Three patients had
LR, all with <3 mm surgical margins. Three patients
noted with late grade 2–3 toxicity.
Levine et al. (2009): Retrospective series of primary
and metastatic spinal sarcomas treated with SBRT,
including 14 primary, largely STS, spinal sarcomas.
Seven patients were treated definitively with SBRT
(24–35 Gy in 3–5 fx) with OS 100 % and LR 29 % at
mean follow up of 33 months. Seven patients received
adjuvant SBRT (3 preoperatively, 4 postoperatively
for +margins), treated with 25–30 Gy in 2–5 fx. Two of
three preoperatively treated patients died of recurrent
disease. OS 100 % for postoperatively treated patients
with median follow-up of 43.5 months. There was one
instance of severe late toxicity involving rectal tumor
cavity fistula in a definitively SBRT-treated patient.
Metastatic STS
Surgical Ablation
Potential survival benefit for ablative treatment of

oligometastatic disease suggested by multiple surgical
series.
Billingsley et al. (1999): MSKCC series of 719 patients
with STS pulmonary metastases. MS 33 months for
patients receiving complete metastatectomy vs. 11

months for those receiving non-operative therapy.
van Geel et al. (1996): Retrospective multi-institu-
tional series of 255 patients with pulmonary STS
metastases. OS 42 and 35 % at 3 and 5 years, respec-
tively. Young age (<40), R0 resection, and low/int
grade tumors associated with better OS.
Porter et al. (2004): Comparative effectiveness study of
surgical metastatectomy vs. systemic chemotherapy
for treatment of pulmonary STS metastases. Despite
favorable assumptions of benefit of chemotherapy,
surgical ablative therapy was deemed a significantly
more cost-effective management approach.
DeMatteo et al. (2001): 331 patients treated at MSKCC
for STS liver metastases. 56 patients underwent R0 or
R1 gross resection of hepatic metastases, with MS 39
months vs. 12 months for those who did not undergo
complete or any resection independent of adjuvant
systemic therapy.
Marudanayagam et al. (2011): Retrospective series of
36 patients who underwent hepatic resection for
oligometastatic STS. OS from metastatectomy was
90.3 % (1 year), 48.0 % (3 years), 31.8 % (5 years).
Poor survival associated with high-grade tumors, pri-
mary leiomyosarcoma, and positive resection margin
of liver metastasis.
Radiotherapy
Merrell et al. (2014): Retrospective series of 21 patients

with metastatic STS receiving SBRT. Median dose
50 Gy in 5 fx (lung), 24 Gy in 1 fx (bone), 42.5 Gy in 5
fx (liver), and 40 Gy in 4 fx (soft tissue). LC was 94
%(12 months), 83 % (24 months), and 83 % (48
months). Most frequent toxicities were of low grade,
including acute pain flare and nausea, and late cough.
Mehta et al. (2013): Retrospective series of 16 patients
treated with SBRT to 25 lesions for high-grade STS
lung metastases. Prescription dose ranged from 36 to

54 Gy in 3–4 fx. LC 94 % at 43 months. No ≥grade 2
pneumonitis or esophagitis.
Stragliotto et al. (2012): Retrospective series of 46
patients with 136 primary sarcoma metastases, includ-
ing 28 patients with STS metastases (mostly lung, liver,
and abdominal/pelvic) treated with SBRT doses of
10–48 Gy in 1–5 fractions. LC 88 % at median follow-
up of 21.8 months. Thirty-one percent of patients dem-
onstrated OS >3 years. Sixty-eight percent of those
treated experienced some toxicity, largely cough and
dyspnea, although there was one incidence of colonic
perforation and one incidence of hip contracture fol-
lowing SBRT.
Dhakal et al. (2012): Retrospective series of 15 patients
treated with SBRT to 74 lesions for STS pulmonary
metastases with preferred dose of 50 Gy in 5 fx. LC 82
% at 3 years. No grade ≥3 toxicity. MS 2.1 year vs. 0.6
years for 37 patients not receiving SBRT for pulmo-
nary STS metastases (p = 0.002).
Corbin et al. (2007): Retrospective series of 58 patients
with STS pulmonary metastases. Sixteen patients
received SBRT to median of 4.5 nodules. OS at 2.5
years was 73 % for SBRT patients vs. 25 % for the
remaining 42 patients treated with EBRT, surgery,
and/or chemotherapy. SBRT found associated with
improved outcome on both univariate (HR = 0.43,
p = 0.012) and multivariate analysis (p = 0.007).
Levine et al. (2009): Retrospective series of primary
and metastatic spinal sarcomas treated with SBRT,
including 10 patients with 16 sarcoma spinal metasta-
ses of various histologies (leiomyosarcoma, chondro-
sarcoma, angiosarcoma, pleomorphic sarcoma) treated
with palliative intent with a median dose 30 Gy in 3 fx.
Patients experienced complete pain relief in 50 %,
partial relief in 44 %, and no relief in 6 % of treated
lesions. MS 11.1 months from time of SBRT.
Folkert et al. (2014): Retrospective series of 88 patients
with 120 sarcoma-related, predominantly STS, spinal
metastases. Patients received hypofractionated

(24–36 Gy in 3–6 fx) or single-fraction (18–24 Gy)
SBRT. LC 87.9 % and OS 60.6 % at 1 year. Single-
fraction was superior to multi-fraction SBRT, with LC
rates of 90.8 % vs. 84.1 %, respectively (p = 0.007). One
percent acute and 4.5 % chronic grade 3 toxicity.
Chang et al. (2005): Retrospective series of 189 patients
treated with SRS for “radioresistant” histologies of
brain metastasis, including melanoma (103), RCC (77),
and sarcoma (9). Median single-session SRS dose was
18 Gy (10–24 Gy), prescribed by tumor size based
upon RTOG 90-05 guidelines. Among patients with
sarcoma metastases, MS was 9.1 month at a median
follow-up of 9.1 months.
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Chapter 12
Extracranial Oligometastases
Jennifer S. Chang, Rajni A. Sethi, and Igor J. Barani
Pearls
The concept of oligometastases was introduced by
Hellman and Weichselbaum in 1995 to describe a state in
which the extent of metastases is limited in number and
location and for which a curative therapeutic strategy
may be indicated (Hellman and Weichselbaum 1995).
Oligometastases are typically defined as 5 or fewer
metastases in a limited number of organ systems.
The incidence of oligometastases is not well known, but
the increased use of PET-CT and other advanced imag-
ing modalities are allowing for the earlier and more
frequent diagnosis of asymptomatic oligometastases.
J. S. Chang () • R.A. Sethi

e-mail: changj@radonc.ucsf.edu
I.J. Barani
University of California, San Francisco, San Francisco, CA, USA

204 J.S. Chang et al.
Given the possibility of long-term survival, oligometa-

static lesions can be treated with definitive rather than
palliative doses.
Common primary tumor sites include colorectal can-
cer, NSCLC (non-small cell lung carcinoma), breast,
soft tissue sarcoma, and renal cell carcinoma.
Common sites of extracranial oligometastasis include
lung, liver, bone, adrenals, and lymph nodes.
Three categories of oligometastatic disease:
Present at diagnosis.
Remaining disease after treatment.
Arising after initial diagnosis/treatment
(oligorecurrence).
Tumor biology likely differs for oligometastatic vs.
widely metastatic disease, with differing genetic signa-
tures and expression profiles (Wuttig et al. 2009;
Lussier et al. 2011).
Surgical series have demonstrated a 5-year survival
of 25–50 % after resection of lung or liver metastases,
and 10–20-year survival rates of 15–25 % in selected
patients, suggesting that definitive treatment of oligo-
metastases can contribute to long-term survival
(Tomlinson et al. 2007, International Registry of
Lung Metastases 1997, Fong et al. 1999, Scheele et al.
1995).
Series of SBRT for oligometastases report 2-year local
control rates of approximately 80 %, 2–3-year disease-
free survival rates of approximately 20 %, and 2–3
years overall survival rates of 25–40 % (Tree et al.
2013; Corbin et al 2013), which is comparable to surgi-
cal series (Tables 12.1 and 12.2).
The majority of local recurrences occur within the first
2 years.
Although the majority of patients will have disease
progression after ablation of oligometastatic disease,
SBRT can serve to delay progression and postpone the
need for additional systemic therapy (Table 12.3).
Table 12.1 Summary of experience with SBRT for treatment of oligometastatic disease to adrenal glands or lymph nodes
Number of Treated Overall
Study Year patients Primary site site Dose Local control survival Toxicity
Casamassima 2012 48 Multiple Adrenal Most 90 % (2 years) 40 % (1 year); No gr3
common 15 % (2 years)
36 Gy/3
fractions
Scorsetti 2012 34 Multiple Adrenal Median 32 % (2 years) MS 22 months No gr3
(most 40 Gy/5
12.
NSCLC) fractions
Oshiro 2011 19 NSCLC Adrenal Median 68 % response 33 % (2 years) No gr3
45 Gy/10 rate
fractions
Holy 2011 18 NSCLC Adrenal 20–40 Gy/5 77 % (2 years) MS 23 months No gr3
fractions
Torok 2011 7 Multiple Adrenal 16 Gy/1 63 % (1 year) MS 8 months NR
(most lung) fraction
or 27 Gy/3
fractions
(continued)
205
206

Chawla 2009 14 Multiple Adrenal 16 Gy/4 55 % (1 year); 44 % (1 year); No gr3
(most lung) fractions to 27 % (2 years) 25 % (2 years)
50 Gy/10
fractions
J.S. Chang et al.
Jereczek- 2014 69 Multiple Lymph Median 81 % (1 year); 50 % (3 years) 3%

Fossa Node 24 Gy/3 64 % (3 years) acute
(Single) fractions gr3; 1 %
late gr4
Choi 2009 30 Uterus Lymph 33–45 67 % (4 years) 50 % (4 years) 3 % late
Node Gy/3fx gr 3–4
(single)
Kim 2009 7 Gastric Lymph Median 29 % (3 years 43 % (3 years) No gr3
Node 48 Gy/3 PFS)
fractions
NSCLC non-small-cell lung cancer, MS medial survival, NR not reported
Table 12.2 Summary of experience with SBRT for treatment of oligometastatic disease to lung or liver
Navarria 2014 76 Multiple Lung 48 Gy/4 89 % (2 years 73 % (2 years); No gr3
fractions and 3 years) 73 % (3 years)
(peripheral);
60 Gy/8
fractions
(central);
60 Gy/3
fractions
(peripheral
<2 cm)
Ricardi 2012 61 Multiple Lung 26 Gy/1 89 % (2 years); 66 % (2 years); 2 % gr3
fraction; 83 % (3 years) 52 % (3 years) pneumonitis
45 Gy/3
fractions;
or 36 Gy/4
fractions
McCammon 2009 141 Multiple Lung Most 100 % (1 year); NR 5 % gr3; 1
60 Gy/3 89 % (3 years) % gr4
fractions if ≥60 Gy
(continued)
Rusthoven 2009(a) 38 Multiple Lung 48–60 100 % (1 year); 39 % (2 years) 8 % gr3
Gy/3fx 96 % (2 years)
Norihisa 2008 34 Multiple Lung 48 Gy/4 84 % (2 years) 90 % (2 years) 3 % gr3
fractions
or 60 Gy/5
fractions
Okunieff 2006 50 Multiple Lung 50 Gy/10 85 % (3 years) 71 % (1 year); 2 % gr3
fractions 255
(3 years)
Chang 2011 65 Colorectal Liver Median 67 % (1 year), 72 % (1 year), 3 % acute
41.7 Gy/6 55 % 92 years) 38 % (2 years) gr3; 6 % late
fractions gr3
Rule 2011 27 Multiple Liver 30 Gy/3 100 % (3 years, 50 %/67 %/56 4 % gr3
fractions; 60 Gy) % (2 years for
50 Gy/5 30 Gy/50 Gy/60
fractions; Gy)
or 60 Gy/5
fractions
van der Pool 2010 20 Colorectal Liver 37.5 Gy/3 74 % (2 years) 83 % (2 years) 10 % gr3
fractions
Goodman 2010 26 Multiple Liver 18, 22, 26, 77 % (1 year) 50 % (2 years) No gr3
or 30 Gy/1
fraction
Rusthoven 2009 47 Multiple Liver Most 95 % 91 years), 30 % (2 years) 2 % gr3
60 Gy/3 92 % (2 years)
fractions
Lee 2009 68 Multiple Liver 24 Gy/6 71 % (1 year) 47 % (18 9 % acute
fractions months) gr3, 1 %
acute gr4;
1 death
from bowel
obstruction
Katz 2007 60 Multiple Liver 50 Gy/5 76 % (10 MS 14.5 No gr3

fractions months), 57 % months
(20 months)
Kavanagh 2006 36 Multiple Liver 60 Gy/3 93 % (18 NR 6 % gr3
fractions months)
Mendez 2006 17 Multiple Liver 37.5 Gy/3 100 % (1 year), 85 % (1 year), 12 % gr3
Romero (most fractions 86 % (2 years) 62 % (2 years) acute, 4 %
colorectal) gr3 late
MS medial survival, NR not reported
210
Table 12.3 Summary of experience with SBRT to mixed oligometastatic sites

Number Primary Treated Overall Toxicity
Study Year of patients site site Dose Local control survival
Comito 2014 82 Colorectal Multiple 48–75 Gy/3–4 80 % (2 years); 65 % (2 years); No gr3
fractions 75 % (3 years) 43 % (3 years)
Jereczek- 2013 95 Multiple Multiple Median 67 % (3 years) 31 % (3 years)
Fossa 24 Gy/3fx
J.S. Chang et al.
Sole 2013 42 Multiple Multiple Median 92 % (1 year), 84 % 91 years), 14 % gr2 or

39 Gy/3fx 86 % (2 years) 63 % (2 years) higher
Bae 2012 41 Colorectal Multiple Median 48 Gy/3 64 % (3 years); 60 % (3 years); No acute gr3;
fractions 57 % (5 years) 38 % (5 years) 7 % late gr3
Salama 2012 61 Multiple Multiple Increasing 67 % (2 years), 81 % (1 year), 3 % acute
24–48 Gy/3 88 % if dose 57 % (2 years) gr3, 10 %
fractions ≥30 Gy late gr3
Milano 2012 121 Multiple Multiple Median 50 Gy/10 74 %/87 % 39 %/74 % 1 % gr3
fractions (2 years non- (2 years non-
breast/breast); breast/breast);
65 %/87 % 9 %/47 % (6
(6 years non- years non-
breast/breast) breast/breast)
Greco 2011 103 Multiple Multiple 18–24 Gy/1 64 % (18 NR 1 % acute
fraction months); 82 % gr3, 3 % late
(18 months, gr3
dose 24 Gy)
Number Primary Treated Overall Toxicity
Study Year of patients site site Dose Local control survival
Kang 2011 59 Colorectal Multiple 36–51 Gy/3 19 % (5 years) 29 % (5 years) 3 % gr4
fractions
Inoue 2010 44 Multiple Multiple 48 Gy/8 fractions 80 % (3 years) 39 % (3 years) No gr3
(mostly (adrenal),
lung) 35–60 Gy in 4–8
fractions (others)
Nuyttens 2007 14 Multiple Multiple Median 7 Gy per 100 % (18 NR No gr3
fraction x Median months)
6 fractions
Svedman 2006 30 Renal cell Multiple 40 Gy/4 fractions 98 % (crude, 52 MS 32 months 2 % gr3
12.
carcinoma most common months median

follow-up)
Hoyer 2006 64 Colorectal Multiople 45 Gy/3 fractions 63 % (2 years) 67 % (1 year), 30 % gr3, 9
38 % (2 years), % gr4
13 % (5 years)
Wersall 2005 58 Renal cell Multiple 30–40 Gy/3 90 % or MS 37 Substantial
carcinoma (mostly fractions most higher (crude, months (1–3 gr3 toxicity
lung) common 37 months metastases), and one
follow-up) 19 months (4+ death from
metastases) gastric
hemorrhage
MS medial survival, NR not reported
211
Factors associated with improved outcomes are:

Number of metastases: Patients with 1–3 metastases
have better PFS than those with 4–5 metastases.
Size: Improved local control of smaller lesions <3 cm.
Dose: BED >100 Gy (α[alpha]/β[beta] ratio = 10)
associated with local control rates of 90 %.
Disease-free interval: Improved survival is correlated
to disease-free intervals of >12 months after SBRT.
SBRT for oligometastatic sites should be considered
when the following criteria are met:
Controlled primary lesion.
5 or fewer metastases.
ECOG ≤2.
Predicted life span at least 3 months.
Work-Up
H&P, Review of Systems, and Laboratories:
These are performed every 3 months in patients
with known metastatic disease. Evaluations focus
on known sites of involvement, as outlined in the
site-specific chapters.
Imaging.
The role and frequency of interval systemic imaging
(PET-CT or CT C/A/P ± contrast ± bone scan) to
survey for development of metastatic disease in
asymptomatic patients is not well defined. High-
risk patients may benefit from surveillance imaging
every 6 months for early detection of oligometa-
static disease.
Patients diagnosed with metastatic disease should
undergo systemic imaging (PET-CT or CT
C/A/P ± contrast ± bone scan, brain MRI) to rule
out additional lesions.
12. Extracranial Oligometastases 213
Refer to site-specific chapters for organ-specific

imaging recommendations for radiation planning.
Pathology.
The first site of metastasis is usually biopsied to
confirm metastatic state. Biopsies of additional
lesions may be performed to confirm sites of metas-
tasis if involvement is unclear based on imaging,
physical exam, and/or laboratory work-up.
Refer to site-specific chapters for simulation, planning,
and dose-delivery recommendations.

Refer to site-specific chapters for toxicity relevant to
different organ systems.
Repeat H&P and PET-CT or CT C/A/P + contrast and
bone scan every 3 months starting 2–3 months after treat-
ment to assess for response and progression of disease.
Evidence
Lung Metastases
Rusthoven et al. (2009a): Multi-institution phase I/II

trial with 1–3 lung metastases up to 7 cm total diameter,
dose escalation from 48 to 60 Gy in 3 fractions. Thirty-
eight patients, 63 lesions, low-burden extrathoracic
disease permitted. Grade 3 toxicity in 8 %, symptom-
atic pneumonitis in 2.6 %. Actuarial local control 100
and 96 % at 1 and 2 years. Median survival 19 months.
Norihisa et al. (2008): Retrospective analysis of 34

patients with 1–2 lung mets from a controlled primary
tumor. Treated with 48 or 60 Gy in 4–5 fractions. Two-
year overall survival 84.3 %, local relapse-free 90 %,
progression-free 34.8 %. No local progression with
60 Gy. Twelve percent grade 2 toxicity, no grade 3.
Longer disease-free interval corresponded to improved
overall survival.
Liver Metastases
Rusthoven et al. (2009b): Phase I/II dose escalation for

47 patients with 1–3 liver mets, each <6 cm. Thirty-six
to sixty Gy in 3 fractions. 92 % in-field control at 2
years, 100 % for ≤3 cm lesions. Two percent ≥grade 3
toxicity. Median survival 20.5 months.
Shefter et al. (2005): Multicenter phase I with 18
patients with 1–3 liver mets, <6 cm max diameter, KPS
>60 %, adequate liver function, no other progressive
or untreated gross disease. Thirty-six to sixty Gy in 3
fractions. ≥700 cc of normal liver with <15 Gy. No
dose-limiting toxicities.
Chang et al. (2011): Multi-institutional cohort study of
65 patients with 1–4 liver mets from colorectal cancer,
treated with 22–60 Gy in 1–6 fractions. Estimated dose
of 46–52 Gy in 3 fractions needed for 1-year local con-
trol >90 %. Nonactive extrahepatic disease correlated
with overall survival.
Adrenal Metastases
Casamassima et al. (2012): Retrospective single-insti-

tution study with 48 patients with adrenal mets (unilat-
eral or bilateral) from various primaries, typically
received 36 Gy in 3 fractions (8 patients treated in
1 fraction, mean 24 Gy; 40 patients treated in 3
fractions, mean 35 Gy). Local control 90 % at 2 years.

Overall survival 39.7 % at 1 year, 14.5 % at 2 years. No
grade 3 toxicity.
Lymph Node Metastases
Jereczek-Fossa et al. (2014): Retrospective single-

institution study with 69 patients (94 lesions) with
metastases to a single abdominal lymph node. Primary
sites were urological, gastrointestinal, gynecologic, and
other. Median follow-up 20 months. Median SBRT
dose was 24 Gy in 3 fractions. Three years local control
64 %, PFS 12 %, and OS 50 %. Failures were predomi-
nantly out of field. Survival rates were significantly
higher (3 years OS 85 %) for prostate or renal cell
primaries. There was 3 % acute grade 3 GU toxicity,
and one patient had late grade 4 toxicity (hemorrhagic
duodenitis).
Studies with Mixed Populations

Salama et al. (2012): Single-institution prospective
dose escalation trial with 61 patients of any histol-
ogy, 1–5 metastases in varying locations, ≤10 cm or
≤500 mL each, life expectancy >3 months, ECOG ≤2.
Dose escalated from 24 to 60 Gy in 3 fractions. Max
tolerated dose not reached. One- and two-year pro-
gression-free survival 33.3 and 22 %, 1- and 2-year
overall survival 81.5 and 56.7 %. Seventy-two per-
cent of patients with progressive disease progressed
in 1–3 sites.
Milano et al. (2012): Prospectively analyzed 121
patients with any primary and 5 or fewer metastases to
1–3 organ sites. For breast primary, 6-year overall sur-
vival 47 %, local control 87 %. For non-breast primary,
6-year overall survival 9 %, local control 65 %.
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Appendix

Radiotherapy, DOI 10.1007/978-3-319-21897-7
One fraction Three fractions Five fractions
Max. critical
vol. in excess Threshold Max. point Threshold Max. point Threshold Max. point Endpoint
Tissue of threshold dose (Gy) dose (Gy) dose (Gy) dose (Gy) dose (Gy) dose (Gy) (≧Grade 3)
Optic <0.2 cc 8 12 15.3 17.4 23 25 Neuritis
pathway (5.1 Gy/fx) (5.8 Gy/fx) (4.6 Gy/fx) (5 Gy/fx)
Cochlea – – 9 – 17.1 – 25 Hearing loss
(5.7 Gy/fx) (5 Gy/fx)
Brainstem <0.5 cc 15 18 18 23.1 23 31 Cranial
(not medulla) (6 Gy/fx) (7.7 Gy/fx) (4.6 Gy/fx) (6.2 Gy/fx) neuropathy
Spinal <0.1 cc 10 14 18 21 23 30 Myelitis
cord + medulla (6 Gy/fx) (7 Gy/fx) (4.6 Gy/fx) (6 Gy/fx)
Cauda equina <5 cc 14 16 21.9 24 30 32 Neuritis
(7.3 Gy/fx) (8 Gy/fx) (6 Gy/fx) (6.4 Gy/fx)
Sacral plexus <5 cc 14.4 16 22.5 24 30 32 Neuropathy
(7.5 Gy/fx) (8 Gy/fx) (6 Gy/fx) (6.4 Gy/fx)
Brachial <3 cc – 24 – 27 27 30.5 Neuropathy
plexus (9 Gy/fx) (5.4 Gy/fx) (6.1 Gy/fx)
Lung (right 1500 cc 7 – 11.6 – 12.5 Gy – Basic lung
and left) (3.87 Gy/fx) (2.5 Gy/fx) function
Lung (right 1000 cc 7.4 – 12.4 – 13.5 Gy – Pneumonitis
and left) (4.13 Gy/fx) (2.7 Gy/fx)
Bronchi, large <4 cc 10.5 20.2 15 (5 Gy/fx) 30 16.5 40 Stenosis/
(incl. trachea) (10 Gy/fx) (3.3 Gy/fx) (8 Gy/fx) fistula
Bronchi, small <0.5 cc 12.4 13.3 18.9 23.1 21 33 Stenosis w/
(6.3 Gy/fx) (7.7 Gy/fx) (4.2 Gy/fx) (6.6 Gy/fx) atelectasis
Chest wall <1 cc 22 30 28.8 36.9 35 43 Pain or
(9.6 Gy/fx) (12.3 Gy/fx) (7 Gy/fx) (8.6 Gy/fx) fracture
Chest wall <30 cc – – 30 – – – Pain or
(10 Gy/fx) fracture
Chest wall <10 cc – – 30 [1] – – – Pain or
(10 Gy/fx) fracture
Chest wall <71 cc to 2 cm – – 30 – 30 – Pain or
chest wall (10 Gy/fx) (6 Gy/fx) fracture
contour
(continued)
(continued)
Max. critical
Esophagus <5 cc 11.9 15.4 17.7 25.2 19.5 35 Stenosis/
(5.9 Gy/fx) (8.4 Gy/fx) (3.9 Gy/fx) (7 Gy/fx) fistula
Stomach <10 cc 11.2 12.4 16.5 22.2 18 (3.6 Gy/ 32 Ulceration/
(5.5 Gy/fx) (7.4 Gy/fx) fx) (6.4 Gy/fx) fistula
Stomach <4 % 22.5 [2] – – 30 [3] – – Ulceration
(10 Gy/fx)
Stomach/ Circumference – 12 – – – – Ulceration/
bowel fistula
Small bowel <30 cc 12.5 [3] – – 30 [3] – – Ulceration/
(10 Gy/fx) fistula
Duodenum <5 cc 11.2 12.4 16.5 22.2 18 (3.6 Gy/ 32 Ulceration
(5.5 Gy/fx) (7.4 Gy/fx) fx) (6.4 Gy/fx)
Duodenum <10 cc 9 – 11.4 – 12.5 Gy – Ulceration
(3.8 Gy/fx) (2.5 Gy/fx)
Duodenum <5 % 22.5 [2] – – – – – Ulceration
Jejunum/ <5 cc 11.9 15.4 17.7 25.2 19.5 35 Enteritis/
Ileum (5.9 Gy/fx) (8.4 Gy/fx) (3.9 Gy/fx) (7 Gy/fx) obstruction
Colon <20 cc 14.3 18.4 24 (8 Gy/fx) 28.2 25 (5 Gy/fx) 38 Colitis/fistula
(9.4 Gy/fx) (7.6 Gy/fx)
Rectum <20 cc 14.3 16 24 (8 Gy/fx) 28.2 25 (5 Gy/fx) 38 Proctitis/
(9.4 Gy/fx) (7.6 Gy/fx) fistula
Rectum Circumference – 14 – – – – Proctitis/
fistula
Rectum <1 cc – – – – 36 [4] – Proctitis/
(12 Gy/fx) fistula
Bladder <15 cc 11.4 18.4 16.8 28.2 18.3 38 Cystitis/
(5.6 Gy/fx) (9.4 Gy/fx) (3.65 Gy/fx) (7.6 Gy/fx) fistula
(continued)
(continued)
Max. critical
Bladder – – – – – – 54 Cystitis/
fistula
Penile bulb <3 cc 14 34 21.9 42 30 (6 Gy/fx) 50 Impotence
(7.3 Gy/fx) (14 Gy/fx) (10 Gy/fx)
Urethra <10 % – – – – 49 [4] 55 Urethral
(9.8 Gy/fx) stricture
Femoral heads <10 cc 14 – 21.9 – 30 (6 Gy/fx) 41.8 Necrosis
(right and left) (7.3 Gy/fx) (8.36 Gy/fx)
Femoral head <5 cc – – – – 25 (5 Gy/fx) – Necrosis
Kidney <2/3 Volume 10.6 – 18.6 – 23 – Malignant
(6.2 Gy/fx) (4.6 Gy/fx) hypertension
Kidney (must <33 % of 10 – 15 (5 Gy/fx) – 18 – Malignant
meet both spared kidney (3.6 Gy/fx) hypertension
constraints) volume
<35 % of total 10 – 15 (5 Gy/fx) – 18 –
kidney volume (3.6 Gy/fx)
Kidney <75 % of 5 [5] – – – – – Not specified
closest kidney
volume
Liver <700 cc 9.1 – 19.2 – 21 – Basic liver
(6.4 Gy/fx) (4.2 Gy/fx) function
Liver <70 % – – – – 30 [6] – Cirrhosis/
(6 Gy/fx) hepatitis
Liver <50 % 5 [2] – – – – – Biliary
stricture
<75 % 2.5 [2]
(continued)
(continued)
Max. critical
Liver Mean – – HCC: 13 [7] – – – Radiation-
(4.3 Gy/fx) induced
liver disease
Mets: 18 [7]
(RILD)
(6 Gy/fx)
Heart <15 cc 16 22 24 (8 Gy/fx) 30 32 38 Pericarditis
(10 Gy/fx) (6.4 Gy/fx) (7.6 Gy/fx)
Great vessels <10 cc 31 37 39 45 47 | 53 Aneurysm

(13 Gy/fx) (15 Gy/fx) (9.4 Gy/fx) (10.6 Gy/fx)
Source: This table summarizes tolerance doses that are largely based on the AAPM Task Group Report 101 (AAPM TG-101) as well as other
sources of primary data, including our own institutional experience. [8-15] Other sources of primary information are cited specifically if based
on smaller reports or early data from limited experience. Please note that most of the doses are unvalidated and based either on toxicity
observations or on mathematical models, and there is a good measure of subjectivity involved as well. Because of the relative absence of
long-term follow-up data for SBRT, it should be recognized that the tolerance data in the table is merely an approximation of normal tissue
tolerance. When treating in areas where there is sparse or absent literature support for toxicity and complications, it is strongly recommended
that formal institutional guidelines and prospective clinical trials with close oversight are implemented
Appendix 229
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230 Appendix
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Index
A AFP. See Alpha-Fetoprotein

AAPM. See American (AFP)
Association of Physicists Albumin, 150
in Medicine (AAPM) Alcohol, 102, 150, 151, 154
AAPM Task Group 101, 24, 32 Alkaline phosphatase, 102, 115, 158
Abdominal compression, 116, Alopecia, 55
137, 152, 161–163 α[alpha]/β[beta] ratio, 169, 197, 218
Ablation, 179, 210 Alpha cradle, 152, 172, 174, 175
Ablative, 2, 3, 202, 203 Alpha-Fetoprotein (AFP), 150
Acoustic neuroma, 4, 6, 45, 52, 56, American Association of
65, 66 Physicists in Medicine
Acromegaly, 2, 51, 68 (AAPM), 24, 33
ACTH. See Adrenocorticotropic American Medical Association
Hormone (ACTH) (AMA), 6–7
Active breathing control (ABC), Amifostine, 177, 181
152, 161, 163 Amygdala, 75
Active surveillance, 170 Amylase, 150
Acute toxicity, 62, 94, 190, 200 Anal, 192
Adenocarcinoma, 115, 153 Analgesics, 106, 122, 160, 190, 191
Adenocarcinoma in situ (AIS), Anaplastic meningioma, 44, 65
115, 130 Androgen deprivation therapy
Adhesions, 158 (ADT), 70
Adrenal Gland, 149, 151, 165, 211 Aneurysm, 47, 107
Adrenal metastases, 115, 153, Angiogram, 56
165, 220–221 Angiosarcoma, 204
Adrenocorticotropic Hormone Anicteric hepatomegaly, 158
(ACTH), 45, 50 Anterior fossa, 63
ADT. See Androgen deprivation Anti-diarrheal, 87, 177
therapy (ADT) Anti-emetic, 87, 200
Aflatoxin, 150 Antimicrobial, 106, 122, 191

Radiotherapy, DOI 10.1007/978-3-319-21897-7
232 Index
AP/PA, 97 Bone, 2, 44, 107, 171, 192,

Apoptosis, 15, 17 201–203, 210, 218, 219
Arc therapy, 28 Bone scan, 171, 172
Arteriovenous malformation Boost, 103, 104, 107, 108, 116, 131,
(AVM), 4, 46–47, 49–51, 158, 170, 175, 176, 180, 181,
54, 56, 69–72 188, 190, 193, 194, 198
Ascites, 158 Bowel, 174, 182, 189, 191, 193,
ASTRO, 4, 84 200, 215
Astrocytoma, 75 bPFS. See Biochemical
Ataxia, 45, 60 progression-free survival
Ataxia telangiectasia, 150 (bPFS)
Ataxia telangiectasia mutated Brachial plexopathy, 106, 122
(ATM), 150 Brachial plexus, 87, 106, 115, 122
ATM-Rad3-related (ATR), 13 Brachytherapy, 108, 170, 178, 181,
Audiometry, 56 188, 190, 193, 201
Autophagy, 15 Bragg-peak, 3
Avoidance structure, 173, 175 Brain metastasis, 4, 43, 58, 205
Brain necrosis, 55
Brainstem, 53, 60, 74
B BRCA, 150
Baclofen, 50 Breast, 14, 214, 216, 221
Betatron, 2 Breast cancer, 2, 3, 5, 43
Bevacizumab, 162 Breath-hold, 116
β galactosidase, 15 Bromocriptine, 50
Biliary stricture, 156 Bronchi, 87, 96
Biochemical failure, 178, 179 Bronchiectasis, 138
Biochemical progression, 181 Bronchodilator, 122
Biological effective dose (BED), Brown-Sécquard syndrome, 84
96, 119, 124, 128, 129, 160, BUN. See Blood urea nitrogen
190, 218
Biochemical progression-free
survival (bPFS), 179–181 C
Biopsy/biopsies, 44, 89, 102, 115, Cabergoline, 50
124, 139, 150, 171, 173, 176, Calculation grid, 28
188, 198, 199 Calvarium, 66
Bitemporal hemianopsia, 45 Capecitabine, 158
Bladder, 170, 171, 174–176, 182 Carbamazepine, 50
Bladder incontinence, 85 Carboplatin, 131
Bleeding, 55, 71, 108, 152, Carcinoembryonic antigen
157, 194 (CEA), 149, 150
Blocking, 73 Carcinomas, 15
Blood-brain barrier, 50 Cardiopulmonary
Blood urea nitrogen (BUN), 102, dysfunction, 121
115, 171, 172, 198 Carotid, 61, 107, 109
Body cast, 24 Carotid artery stenosis, 61
Body frame, 24, 26, 189, 199 Cauda equina, 85
Index 233
Cause-specific survival (CSS), 61, Cirrhosis, 156

62, 127 Cisplatin, 107, 108, 132, 193
Cavernous malformations, 46, CK. See CyberKnife™ (CK)
55, 72 c-kit, 197
Cavernous sinus, 45 Clinical trial, 12, 84
CBC. See Complete blood count Clinical target volume (CTV), 26,
(CBC) 86, 103, 118, 153, 159–161,
CBCT. See Cone beam computed 163, 173, 175, 192, 194,
tomography (CBCT) 199, 200
CEA. See Carcinoembryonic Clivus, 94
antigen (CEA) Clonogenic assay, 14
Cell division, 15 Cluster headache, 47
Cell sensitizers, 12 CMP. See Comprehensive
Cell survival, 15–18 metabolic panel (CMP)
Cement kyphoplasty, 84 CMS. See Centers for Medicare
Central Airway, 120 and Medicaid Services
Central nervous system (CNS), 2, (CMS)
6, 48, 83 CN. See Cranial nerve (CN)
Centers for Medicare and CNS. See Central nervous system
Medicaid Services (CNS)
(CMS), 7 Cobalt gray equivalent (CGE), 93
Centromeres, 15 Coccyx, 83
Cerebellopontine angle (CPA), Collimator, 27, 29, 36
45, 47, 56, 64 Colon, 139
Cerebral aneurysm, 46 Colonic perforation, 204
Cerebral vasculopathy, 68 Colorectal, 116, 164, 210, 215, 220
Cerebrospinal fluid (CSF), 68 Commissioning procedures, 24
Cervical cancers, 192 Comorbidities, 121, 127, 198
Cervix, 192–194 Complete blood count (CBC),
Cetuximab, 109, 110 85, 102, 115,, 150, 171, 172,
CGE. See Cobalt gray equivalent 188, 198
(CGE) Complete response (CR), 47, 75,
Chemodectomas, 45 163, 171
Chemoradiation, 109, 114, 116, Complications, 61, 67, 70,
131, 151 177, 201
Chemoreceptors, 45 Composite planning, 190
Chemotherapy, 110, 131–132 Comprehensive metabolic panel
Chest wall, 116, 117, 126, 129, 135 (CMP), 85
Chest X-ray (CXR), 137–139, 172 Compression fracture, 87
Childs-Pugh, 150 Computerized tomography (CT),
Child-Turcotte-Pugh, 162 90, 102, 107, 113–115, 117,
Choline, 51, 181 118, 123, 124, 135, 137, 138,
Chondrosarcoma, 83, 89, 93, 204 150, 152–155, 158, 159, 161,
Chordoma, 86, 93–95 163, 171–175, 188, 189, 192,
Choriocarcinoma, 51 198–201, 209, 218, 219
Chromosome 22q, 44 Cone beam, 25, 33, 34, 165, 200
234 Index
Cone beam computed CT simulation, 86

tomography (CBCT), CTV. See Clinical target volume
31–33, 87, 102, 105, 136, (CTV)
174, 190, 194 Cumulative dose, 74, 107
Conformality index, 60 Current procedural terminology
Conjunctival injection, 47 (CPT), 6
Contrast, 51, 102, 103, 115, 150, Cushing disease, 68
152, 188, 192, 199, 218, 219 CXR. See Chest X-ray (CXR)
Control rate, 5, 6, 62, 65, 68, 92, CyberKnife™ (CK), 169
108, 110, 127, 134, 187, 210, Cyclotron, 2
218 Cyst, 61, 68, 71
Conventional fractionation, 12 Cystitis, 177, 190
Convolution, 28, 118, 137 Cystoscopy, 171, 175
Coplanar, 27, 30
Co-registration, 51, 86
Cost-effectiveness, 127 D
Couch, 30, 33, –34, 36, 116 Death(s), 45, 72, 75, 101, 106, 108,
Cough, 115, 121, 122, 135, 203, 110, 113, 123, 131, 134, 135,
204 158, 159, 163, 179, 197, 215,
CPA. See Cerebellopontine angle 217
(CPA) Demyelination, 47, 51
CPT. See Current Procedural Dermatitis, 105, 122, 191
Terminology (CPT) Desmoid, 199
Cr. See Creatinine (Cr) Desquamation, 191
CR. See Complete response Dexamethasone, 43, 50
(CR) Diaphragm, 117, 161
Cramping, 157 Diarrhea, 157, 192, 194
Cranial nerve (CN), 45, 47, 55, 61, Digestive system, 149
64–68 Digitally reconstructed
Cranial nerve palsies, 45 radiograph (DRR), 31, 174
Craniofacial pain syndrome, 48 Digital rectal examination
Craniopharyngiomas, 48 (DRE), 171, 177
Craniotomy, 62 Diode, 37
Creatinine (Cr), 51 Disease-free interval, 218
Critical structures, 52, 62, 149, Disequilibrium, 60
152 Displacement, 161
Cryotherapy, 151 Distance indicator (ODI), 36
CSF. See Cerebrospinal fluid Distant metastasis, 187
(CSF) Dizziness, 107
CSF leak, 68 Dmax, 91, 92, 96, 120, 155, 157,
CSS. See Cause-specific survival 159, 176
(CSS) DNA, 11, 14, 15
CT. See Computerized Dose, 25–29, 32, 52–54, 57, 86, 87,
tomography (CT) 91–92, 95, 104–105,
CT myelogram, 85, 86 118–120, 134, 153–157, 161,
Index 235
162, 164, 175–177, 181, Endoscopic endonasal

189–190, 192–194, 199, 200, transsphenoidal resection,
211, 216, 218, 221 90
escalation, 54, 114, 131, 132, Endoscopic ultrasound (EUS),
134, 160, 179, 193, 219–221 150, 152
gradient, 25, 27 End-to-End validation tests, 34
heterogeneity, 26 Enema, 172
rate, 29 EORTC. See European
reduction, 53 Organisation for Research
volume histogram, 26, 70, 121 and Treatment of Cancer
Dose-response, 14, 15, 86 (EORTC)
Doxorubicin, 197 Ependymoma, 75, 84
DRE. See Digital rectal EPID. See Electronic portal
examination (DRE) imaging (EPID)
DRR. See Digitally reconstructed Epidural, 83, 84, 88, 91
radiograph (DRR) Epilepsy, 48, 75
Duodenitis, 221 Equivalent dose in 2 Gy fractions
Duodenum, 155 (EQD2), 97, 193
Dural tail sign, 51 Erectile dysfunction, 177
Dynamic conformal arcs, 27 Erythema, 191
Dysesthesias, 74 Erythrocyte sedimentation rate
Dyspepsia, 157 (ESR), 198
Dysphagia, 76, 92, 102, 106, 110 Esophageal stricture, 106, 123
Dyspnea, 115, 121, 122, 135, 204 Esophagitis, 87, 135, 204
Esophagus, 87, 119
ESR. See Erythrocyte
E sedimentation rate (ESR)
Eastern Cooperative Oncology Essential tremor, 48, 76
Group (ECOG), 136, 218, EUA. See Exam under
221 anesthesia (EUA)
EBRT. See External beam European Organisation for
radiation therapy (EBRT) Research and Treatment
ECOG. See Eastern Cooperative of Cancer (EORTC), 59,
Oncology Group (ECOG) 65
ECOG performance status, 59 EUS. See Endoscopic ultrasound
Edema, 50, 55, 63, 152, 159, 202 (EUS)
EGFR mutation, 115 Exam under anesthesia (EUA),
Electronic disequilibrium, 28 171
Electronic portal imaging External beam radiation therapy
(EPID), 24, 172, 174, 180 (EBRT), 93, 97, 102, 104,
Eloquent, 46, 70 107, 108, 114, 135, 136, 180,
Endocrinopathy, 64 187–189, 193, 194, 197–200,
Endometrial, 192–194 204, 207
Endometrium, 194 Extremity, 198
Endoscopic, 150 Eye dryness, 55
236 Index
F Fractionated conformal
Facial nerve, 45 radiotherapy (FCRT), 92
Facial numbness, 47, 60, 67, 73, Frame-based SBRT, 163
107 Frameless radiosurgery, 24
Facial palsy, 55 Free cortisol, 50
Facial paresis, 45 Free-breathing, 117
Facial paresthesia, 72 FSH. See Follicle-stimulating
Fatigue, 55, 121 hormone (FSH)
FCRT. See Fractionated Functional adenoma, 69
conformal radiotherapy Functional status, 61, 201
(FCRT) Fusion, 52, 103, 173, 189, 199
FDG. See Fluoro-deoxy-glucose
(fludeoxyglucose) (FDG)
Femoral head, 176 G
Fever, 121 G2/M, 14
Fibrosis, 110, 123, 138, 158, 200, Gabapentin, 50
202 Gadolinium, 50, 51, 85, 103
Fiducial, 31, 66, 86, 87, 136, 154, Gamma Knife, 2, 28, 93
160, 172, 174, 178, Gamma Knife radiosurgery
189, 199 (GKRS), 47, 57–59, 62–65,
Field-in-field, 28 67, 69, 71–76
Fine needle aspiration (FNA), Gardner’s syndrome, 197
102, 188 Gastrointestinal, 221
Fistula, 96, 106, 110, 123, 155, 191, Gastrointestinal stromal tumor
192, 202 (GIST), 197, 198
5-fluorouracil (5FU), 158 Gating, 26
Fletcher, G., 5 Gaze palsy, 75
Fluid attenuation inversion Gemcitabine, 159
recovery (FLAIR), 50 Genitourinary, 169–182
Fluoro-deoxy-glucose Germ cell tumor, 75
(fludeoxyglucose) (FDG), GGO. See Ground glass object
123, 160 (GGO)
FNA. See Fine needle aspiration GIST. See Gastrointestinal
(FNA) stromal tumor (GIST)
FOLFIRINOX, 160 GKRS. See Gamma Knife
Follicle-stimulating hormone radiosurgery (GKRS)
(FSH), 50 Gleason score (GS), 173
Foramen magnum, 51, 83 Glial tumors, 48
Forbes-Albright syndrome, 45 Glioblastoma, 14, 84
Forward planning, 27 Gliosis, 50
4D CBCT, 31 Glomus tumors, 45
Fractionated, 11, 17, 61, 62, 65, 66, Gold seed markers, 172, 174, 175
68, 92–94, 103, 108, 114, Gross total resection, 89, 90
135, 136, 151 Ground glass object (GGO),
Fracture, 157 123, 138
Index 237
GS. See Gleason score (GS) Hormone replacement therapy, 68

GTV, 26, 52, 86, 89, 103, 118, 129, Horner’s syndrome, 115
152, 159, 161–164, 173, 175, Hounsfield unit, 33
189, 193, 199 Human papillomavirus (HPV),
Gynecologic, 187–194, 221 102
Hydrocephalus, 45
Hyperbaric oxygen, 87, 106, 123
H Hyperbilirubinemia, 192
Handwriting score, 76 Hyperesthesia, 55, 72
HDR. See High dose rate (HDR) Hyperostosis, 51
Head and neck squamous cell Hyperpigmentation, 191
carcinoma (HNSCC), 108, Hypertension, 156
109 Hypofractionation, 48, 67, 68
Head frame, 24 Hypopharynx, 109
Headache, 47 Hypopituitarism, 68, 69
Hearing loss, 45, 67 Hypoxia, 12, 121, 135
Hearing preservation, 53, 65–67
Heart, 119
Helical tomotherapy, 28 I
Hemoptysis, 106, 115, 123 ICRU. See International
Hematuria, 172 Commission on Radiation
Hemorrhage, 69–72, 106–108, Units and Measurements
110, 123, 135, 217 (ICRU)
Hepatectomy, 151, 163 IDL. See Isodose line (IDL)
Hepatitis, 150 Ifosfamide, 197
Hepatitis B, 150 iGTV. See Internal gross tumor
Hepatitis C, 150 volume (iGTV)
Hepatocellular carcinoma, 154, Ileus, 193
164 Image-guided, 91, 202
Hereditary hemochromatosis, 150 Imaging, 1, 24, 26, 31–35, 55, 56,
Heterogeneity, 28, 104, 110, 137 84, 90, 116, 117, 124, 136,
High dose rate (HDR), 170, 178, 150, 152, 161, 171, 172, 190,
181, 194, 201 199, 201, 209, 218, 219
Hippocampus, 75 Imatinib, 198
Histology, 57, 60, 61, 97, 118, 150, Immobilization, 4, 24, 26, 52, 85,
221 91, 152, 160
HNSCC. See Head and neck Immobilization device, 24, 26, 85
squamous cell carcinoma Impotence, 45
(HNSCC) IMRT. See Intensity-modulated
Hoarseness, 115 radiation therapy (IMRT)
Homogeneity, 178 Induration, 110
Homologous recombination In-field recurrence, 114
(HR), 12 Inflammation, 157
Hopkins Verbal Learning Test, 58 Infrared imaging, 25
Hormone, 46, 68, 69 Inferior vena cava (IVC), 88, 172
238 Index
INR. See International K

normalized ratio (INR) Karnofsky Performance Scale
Intravenous (IV), 189 (KPS), 44, 48, 49, 56–58,
Intravenous pyelogram (IVP), 171 132, 151, 220
Intensity-modulated radiation Kidney, 156
therapy (IMRT), 28, 34, 92, KPS. See Karnofsky Performance
158, 159, 169, 170, 181, 194, Scale (KPS)
201, 202 kV cone beam CT, 25, 161
Inter-fraction, 161 kV fluoroscopy, 152, 161
Internal gross tumor volume kV imaging, 34
(iGTV), 117, 118, 199 kV x-ray, 172
Internal target volume (ITV), 25,
26, 118, 137, 152, 153, 160,
165, 175, 199, 200 L
International Commission on Lactate, 51
Radiation Units and L’hermitte’s syndrome, 122
Measurements (ICRU), Lactate, 51
26, 27 Lactate dehydrogenase (LDH),
International normalized ratio 102, 115, 150, 172, 198
(INR), 150 Landmark-based registration
Intracranial tumor, 43–45, 52 algorithm, 74
Intra-fraction, 161, 174 Laparoscopy, 158
Intraoperative radiation therapy Laparotomy, 152, 158
(IORT), 198 Large bowel, 155
Inverse planning, 27 Larynx, 104, 108, 109
Iris, 35 Laser, 179
Isocenter, 29, 32–34, 36, 52, 74 Late toxicity, 92, 93, 134, 181,
Isodose line (IDL), 25, 54, 66, 190, 202
88–90, 92–94, 96, 104, 109, Latency period, 69–71
119, 153–155, 162, 164, 165, LDH. See Lactate
173, 190, 192, 193 dehydrogenase (LDH)
Isointense, 51 Leiomyosarcoma, 203
ITV. See Internal target volume Leptomeningeal, 75
(ITV) LF. See Local failure (LF)
IV. See Intravenous (IV) LFT. See Liver function test (LFT)
IVC. See Inferior vena cava LH. See Luteinizing hormone
(IVC) (LH)
IVP. See Intravenous pyelogram Lhermitte’s syndrome, 90
(IVP) Lidocaine, 122
Life expectancy, 127, 221
Lifetime risk of hemorrhage, 46
J Li-Fraumeni syndrome, 197
Jaw, 105, 107 Linear accelerator, 3, 57, 169,
Japanese Radiation Oncology 178–180
Study Group (JROSG), 58 Linear quadratic equation, 12
Joint stiffness, 202 Lipase, 150
Index 239
Liver, 4, 5, 115, 149, 150, 152, 153, Meningioma, 44, 47, 49, 56, 61, 62,
160–164, 188, 192, 197, 200, 64, 65, 84
203, 204, 210, 213–215, 220 Meta-analysis, 132
function, 150, 153, 188, 220 Metastasis, 43, 88, 203, 219
metastases, 203, 210 Metrizamide, 85
Liver function test (LFT), 188 Microadenoma, 45
Lobectomy, 114 micro-MLC, 30, 35, 37
Local failure (LF), 92, 93, 108, Microsurgery, 65
125, 165, 185 Microvascular decompression,
Low residue diet, 177 50, 73
Lumbar plexus, 87 Mini–mental state examination
Lung, 26, 113, 119, 120, 124–135, (MMSE), 58
138, 139, 199, 210, 213, 214, MIP. See Maximum intensity
219–220 projection (MIP)
Lung cancer, 5, 43, 113, 114, 123, MMSE. See Mini–mental state
131, 135, 138, 212 examination (MMSE)
Luteinizing hormone (LH), 50 Monitor units (MU), 36
Lymph node, 149, 151, 153, 164, Monte Carlo, 28, 118, 137
171, 187, 210–212, 221 Movement disorders, 2, 3
Lymphedema, 200 MRA. See Magnetic resonance
angiogram (MRA)
MRI, 47, 50–52, 55, 56, 75, 85, 86,
M 90, 102, 103, 106, 115, 122,
Macroadenoma, 45, 50 150, 152, 161, 171–173, 175,
Magnetic resonance angiogram 176, 180, 188, 189, 198, 199,
(MRA), 51 201, 218
Magnetic resonance MTD. See Maximum tolerated
spectroscopy, 51 dose (MTD)
Malabsorption, 157 MU. See Monitor units
Malnutrition, 110 Mucositis, 110, 160
Mandible, 104 Multileaf collimator, 27
Margin, 24 Multiphasic, 150, 158, 163
Marker, 154, 199 Multiple-mole melanoma
Maximum intensity projection syndrome, 150
(MIP), 117 Multivariate analysis, 56, 57, 59,
Maximum tolerated dose 62, 71, 73, 95, 161, 163, 204
(MTD), 57 Muscle, 171
Mediastinoscopy, 115 MV. See Megavoltage (MV)
Mediastinum, 102 Myelitis, 157
Medullary thyroid cancer, 89 Myelogram, 199
Medulloblastoma, 48 Myelopathy, 87, 90, 91, 93, 96, 200
Megavoltage (MV), 1
Meiosis, 47
Melanoma, 43, 51, 205 N
Memory impairment, 55 N-acetylaspartic acid (NAA), 51
Meninges, 51 Nadir, 178, 180, 181
240 Index
NaF PET/CT, 171 O

NAGKC, 63, 64 Obesity, 150
Narcotic, 91 Obliteration, 46, 54, 69–71, 158
Nasal congestion, 47 Obstruction, 45, 158, 164, 191, 215
Nasopharyngeal carcinoma, 88 Occlusion, 158
Nasopharynx, 108, 109 Occupational therapy, 106, 122
National Comprehensive Cancer Optical distance indicator
Network (NCCN), (ODI), 36
171, 177 Oligometastasis, 210
Nausea, 87, 92, 157, 160, Opiates, 193
191, 203 Optic chiasm, 45
NCCN. See National Oral cavity, 104, 108, 109
Comprehensive Cancer Oral contrast, 189
Network (NCCN) Organs at risk (OAR), 103, 118
Neck, 108–109 Oropharynx, 108
Necrosis, 3, 15, 51, 55, 87, Osteoradionecrosis, 107
106–108, 158, 191 Output constancy, 36
Nelson syndrome, 68 Ovarian, 139
Neoadjuvant, 95
Nephrectomy, 170
Neuralgia, 52, 54, 73 P
Neurectomy, 73 Pacemaker, 85
Neurocognitive testing, 58 Pack-year, 113, 138
Neurocytoma, 48 Paclitaxel, 131
Neuroendocrine tumor, 45 Pain, 2, 3, 45, 47–51, 56, 72–74,
Neuropathic pain, 106, 122 84–86, 91–94, 97, 106, 115,
Neuropathy, 188 121, 123, 126, 129, 130, 150,
Neurotoxicity, 57 151, 158, 160, 171, 172, 188,
NHEJ. See Non-homologous end 192, 200, 203, 204
joining (NHEJ) Pain syndromes, 2, 3, 49
Nidus, 46, 69, 71 Palliation, 91, 151
Nitroimidazoles, 12 Palliative radiotherapy, 89, 97
Non-coplanar, 27, 30, 173 Pancoast, 115
Non-functioning pituitary Pancreas, 150–153, 158
adenomas, 68 Pancreatic cancer, 149, 158–160
Non-homologous end joining Pancreatic tumor, 152
(NHEJ), 12 Papillary epithelial tumor, 75
Non-isocentric, 27, 105, Pap-smear, 192
120, 173 Paraganglioma, 45, 53, 67–68
Non-small cell lung cancer Parahippocampal gyrus, 75
(NSCLC), 113–117, 119, Paralysis, 84
124–139, 211 Paranasal sinus, 109
North American Gamma Knife Paresis, 45, 91
Consortium, 94 Parkinson disease, 48, 76
NSAID, 122 Parotid, 104
Index 241
Particle radiation, 28 Positive margins, 198

PDD. See Percent depth dose Positron emission tomography
(PDD) (PET), 86, 114, 124, 131,
Pedicles, 86, 91, 96 160, 181, 188, 189, 192, 199,
Pelvic exam, 192 201, 209, 218, 219
Pencil beam algorithms, 28 Posterior elements, 96
Penile Bulb, 176 Post-obstructive pneumonia, 115
Penumbra, 27 Pre-sacral space, 86
Percent depth dose (PDD), 34 Prescription, 25, 86, 96, 104,
Perfexion, 29, 30 118–119, 153–155, 173,
Performance status, 59, 102, 114, 189–190, 200, 204
149, 152, 160, 188 Prescription Isodose Line, 25, 173
Pericarditis, 157 Primary spinal cord
Peri-orbital edema, 55 neoplasms, 84
Peritumoral edema, 64, 198 Primary spinal cord tumors, 83
PET. See Positron emission Pro angiogenic factor, 13
tomography (PET) Proctitis, 179, 191
Petroclival meningioma, 64 Prolactin, 46, 50
Peutz-Jeghers syndrome, 150 Prolactinoma, 45, 68
Phantom, 35 Prostate, 139, 169–173, 175–178
Pharmacotherapy, 106, Prostate cancer, 5, 173, 181
121–123, 200 Prostate-specific antigen (PSA),
Phenazopyridine, 190 171, 173, 177–181
Phenytoin, 50 Proton, 66–67
Phoenix definition, 178 PSA “bounce”, 178
photons, 3, 27, 29, 88–90, 153, 154 PSA nadir, 178, 180, 181
Pineal parenchymal tumors, 48, Psoas muscle, 88
74, 75 Pterygopalatine ganglion,
Pineal tumor, 54 47, 48
Pineoblastoma, 74 Ptosis, 47
Pineocytoma, 74 PTV. See Planning target volume
Pinpoint chamber, 37 (PTV)
Pituitary adenoma, 50, 51, 54, 56 Pulmonary function, 136
Pituitary infundibulum, 46
Planning target volume (PTV),
25, 26, 86, 90, 91, 96, 103, Q
104, 118, 119, 135–137, Quality assurance, 24, 32, 35
152–154, 159, 160, 162–165, Quality-adjusted life year, 127
173, 175, 189, 192–194, 200 Quality of life (QOL), 160
Pleural effusion, 115, 134
Pneumonectomy, 131, 136
Pneumonitis, 96, 122, 125, 128–131, R
134–136, 204, 213, 220 Radiation sickness, 6
Pons, 52 Radiation-induced liver disease
Porta hepatis, 154 (RILD), 156, 158, 161
242 Index
Radiation Therapy Oncology Response criteria, 149

Group (RTOG, 44, 56, 57, Retinoblastoma, 197
65, 97, 118, 119, 125, 126, Retinopathy, 107
137, 164, 172, 176, 205, ) Retroperitoneal, 164, 198
protocols, 118 Review of systems, 49, 85, 150, 188
Radiculopathy, 93 RFA. See Radiofrequency
Radiofrequency ablation (RFA), ablation (RFA)
73, 151, 164 Rhinorrhea, 47
Radiofrequency tracking, 25 Rib fracture, 123, 128, 130, 158
Radionecrosis, 3, 57, 75 RILD. See Radiation-induced
Radiosensitivity, 14, 17 liver disease (RILD)
Radiosurgery, 2, 4, 24, 28, 35, 50, Rinne test, 49
52–54, 61, 66, 67, 70–72, 76, RPA. See Recursive partitioning
88–90, 93, 94, 153, 154 analysis (RPA)
Radiosurgery (RS), 4, 66–67 RS. See Radiosurgery (RS)
RapidArc, 28 RTOG. See Radiation Therapy
RBE. See Relative biological Oncology Group (RTOG)
effectiveness (RBE)
RCC. See Renal cell carcinoma
(RCC) S
RECIST, 123 SABR. See Stereotactic ablative
Rectal cancer, 182 brain radiation (SABR)
Rectal ulcer, 177 Sacrum, 95
Rectovaginal fistula, 191 Salvage, 59–61, 84, 181
Rectum, 86, 173 Salvage treatment, 48, 49, 71
Recursive partitioning analysis Sarcoma, 116, 204, 205, 210
(RPA), 44, 49, 56, 58–60 SBRT. See Stereotactic body
Redistribution, 5, 11, 17 radiotherapy (SBRT)
Reflective markers, 24 Schwann cells, 44
Re-irradiation, 91, 93, 97, 104, 106, Schwannoma, 84
116, 119, 123, 135, 187, 190 Sciatic neuropathy, 95
Relative biological effectiveness Second primary, 136
(RBE), 66, 70 Secondary malignancy, 200
Renal, 169, 170, 172, 175, 176, SEER, 127
182, 217 Segmentectomy, 117
Renal cell carcinoma (RCC), Seizure, 43, 75
5, 116, 169, 170, 176, 182, Seizure prophylaxis, 43
205, 217 Seminal vesicle, 173
Renal Cortex, 176 Sensorineural hearing loss, 49
Renal function, 182 Sensory changes, 49, 85, 106, 122
Renal Hilum, 176 Setup accuracy, 91
Reoxygenation, 5, 6, 11, 12, 17 Sex hormones, 44
Repair, 5, 11, 13, 14, 17 Sexual function, 182
Repopulation, 5, 11, 13, 17 SF. See Surviving fraction
Respiratory gating, 116, 162, 199 Shortness of breath, 121
Respiratory motion, 25, 31 Simpson grading system, 44
Index 243
Simulation, 24, 152, 172, 189, 219 Stereotactic body radiotherapy

Single metastasis, 56 (SBRT), 1, 3–6, 12–17,
Skin, 106, 120, 126, 191 24–26, 28–30, 32, 34–37, 84,
Skin necrosis, 106 85, 87–93, 95–97, 101,
Skull base paraganglioma, 67 103–105, 107–110, 114–116,
Skull base tumor, 55 119, 120, 123–128, 131, 132,
Slice thickness, 33, 86 134–138, 149, 151–154,
Sluder’s Neuralgia, 48 158–165, 169, 170, 173,
SMA. See Superior mesenteric 175–182, 187–190, 192–194,
artery, (SMA) 198–205, 210–218, 221
Small bowel, 155 Stereotactic head frame, 32
Small cell lung cancer, 116 Stereotactic markers, 181
Small field dosimetry, 34 Stereotactic radiosurgery (SRS), 1,
Smoking, 102, 109, 113, 114, 3–5, 12–17, 24–26, 28–30, 32,
121, 138 34–37, 46–50, 52, 54–63,
Soft tissue sarcoma (STS), 197, 65–70, 72–75, 93–95, 197, 201
198, 201–205 Steroids, 43, 55, 57, 71, 75, 84, 106,
Sorafenib, 151, 164 121, 122, 191
Spatial resolution, 33 Stomach, 155
Speech impairment, 76 STR. See Subtotal resection
Spetzler–Martin grade, 50, 69–71 (STR)
Sphenoid, 48 Stroke, 55
Sphenopalatine ganglion, 48 STS. See Soft tissue sarcoma
Spinal canal, 83, 91 (STS)
Spinal cord, 83–85, 87, 91–93, 96, Sublobar resection, 114, 126, 127
104, 105, 109, 119 Subtotal resection (STR), 50, 62
Spinal cord compression, 93 Sulfamethoxazole, 121
Spinal cord myelopathy, 96 Superior mesenteric artery,
Spinal sarcoma, 202, 204 (SMA), 152
Spinal segments, 95 Superior sulcus tumor, 115
Spine, 5, 31, 84, 85, 87, 89, 90, Supportive care, 106, 122, 151,
94–97, 106, 107, 122, 157, 191
189, 200 Surgery, 13, 50, 51, 59, 61, 63, 64,
Spine tracking, 189 67, 69, 70, 72, 74, 95, 102,
Spinous process, 85 126, 127, 132, 149, 151, 159,
Spontaneous hemorrhage, 46, 69 165, 194, 197, 198, 204
Square field output, 34 Surveillance, 49, 84, 170, 192, 218
SRS. See Stereotactic Surviving fraction (SF), 15
radiosurgery (SRS) SVC syndrome, 115
Staged AVM treatment, 71, 72
Staged SRS, 69
Standard fractionation, 5, 84 T
Stenosis, 157, 191 Tamsulosin, 177
Stent, 106, 150 Target localization, 32
Stereotactic ablative brain Target motion, 161
radiation (SABR), 7 Temporal lobe, 75, 107, 108
244 Index
Testosterone, 50 Tumor vascular thrombosis

Thalamotomy, 76 (TVT), 163
Thecal sac, 96, 97 TURBT. See Transurethral
Therapeutic ratio, 5 resection of bladder tumor
Thermoplastic mask, 24 (TURBT)
Thoracentesis, 115 TURP. See Transurethral
3-dimensional conformal resection of prostate
radiation therapy (TURP)
(3D-CRT), 28 TVT. See Tumor vascular
Thyroid, 89, 116 thrombosis (TVT)
Thyroid-stimulating hormone
(TSH), 45, 50
TIA. See Transient ischemic U
attack (TIA) UA. See Urinalysis (UA)
Tinnitus, 45, 67 Ulceration, 87, 135, 157, 160
Tobacco, 138, 150 Ultrasound, 31, 102
Tocopherol, 106, 123 Unflattened beams, 27
Tomotherapy, 29, 30 Universal survival curve (USC), 16
Topical moisturizer, 106, 122 Ureteral stricture, 191
Total bilirubin, 150 Ureteroscopy, 171
Tracheo-esophageal fistula, 123 Urethra, 171, 173, 190
Track algorithms, 34 Urethral stricture, 177
Transaminitis, 158 Urethritis, 190
Transarterial Urinalysis (UA), 171, 172
chemoembolization, Urine cytology, 171
151, 164 Urogram, 171
Transient ischemic attack Urothelial carcinoma, 182
(TIA), 107 USC. See Universal survival
Transplant, 151 curve (USC)
Transrectal ultrasound (TRUS), USPSTF, 113
171, 172
Transurethral resection of
bladder tumor (TURBT), V
171, 182 Vaginal bleeding, 188
Transurethral resection of Vaginal dilator, 191
prostate (TURP), 177, 179 Validation measurement, 34
Tremor, 76 Variable aperture collimator, 29
Trigeminal nerve, 47, 51, 52 Varian (in relation to Linac-
Trigeminal neuralgia, 47, 55, 64, based systems), 31
72–74 Vascular endothelial growth
Trigone, 171 factor (VEGF), 13
Trimethoprim, 121 Vascular malformations, 69–72
Triphasic, 150, 152 Vasculopathy, 106, 123
TrueBeam, 31 Vasomotor activity, 48
TSH. See Thyroid-stimulating VEGF. See Vascular endothelial
hormone (TSH) growth factor (VEGF)
Index 245
Venous sinus (es), 44 Vocal cord paralysis, 67, 95

Ventralis intermedius, 76 Volume averaging, 37
Versa, 31 Volumetric-modulated arc
Vertebral body, 88, 95, 96 therapy (VMAT), 28
Vertebral body compression Vomiting, 87, 157
fracture, 87, 95
Vertigo, 45, 67
Vesicovaginal fistula, 191 W
Vestibular nerve, 44 Weber test, 49
Vestibular schwannoma, 44, 47, Wedge resection,
65, 66 114, 126
Vision loss, 55 World Health Organization
Visual field testing, 56 (WHO), 53, 61
VMAT. See Volumetric-modulated Wingboard, 152
arc therapy (VMAT) Winston-Lutz test, 32

Handbook of Evidence Based SRS and SBRT 2016

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Handbook of Evidence Based SRS and SBRT 2016

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Rajni A. Sethi · Igor J.

Rajni A. Sethi, MD Igor J. Barani, MD

ISBN 978-3-319-21896-0 ISBN 978-3-319-21897-7 (eBook)

Library of Congress Control Number: 2015945109

Springer Cham Heidelberg New York Dordrecht London

Printed on acid-free paper

Springer International Publishing AG Switzerland is part of Springer

Over the past decade, technical advancements in radiother-

of SRS or SBRT, guide treatment technique, and summarize

We want to sincerely thank the contributing authors for

San Francisco, CA, USA Rajni A. Sethi, MD

AAPM American Association of Physicists in Medicine

COPD Chronic obstructive pulmonary disease

FNA Fine needle aspiration

PALN Para-aortic lymph nodes

TIA Transient ischemic attack

1 Introduction to Stereotactic Radiosurgery

Part I Radiobiology of Stereotactic Radiosurgery

2 Radiobiology of Stereotactic Radiosurgery

Part II Physics of Stereotactic Radiosurgery

3 Physics of Stereotactic Radiosurgery

Part III Clinical Applications

4 Intracranial Tumors ..................................................... 41

6 Head and Neck ............................................................ 97

Appendix A: Dose-Volume Criteria ................................. 221

I-Chow Joe Hsu, MD

Stereotactic radiosurgery (SRS) and stereotactic body radio-

D.A. Larson ()

© Springer International Publishing Switzerland 2016 1

in six fractions over 2 weeks to ablate the pituitary without

Development of SRS and SBRT

radiation oncologists and neurosurgeons at the first North

Standard Fractionation Versus

For small tumors such as acoustic neuromas, meningiomas,

(RVS) Update Committee (RUC), the Centers for Medicare

Historically, the radiation biology relevant to clinical treatment

A. Vaughan (*) • S.S.D. Rao

© Springer International Publishing Switzerland 2016 11

separate normal tissue toxicity from that seen in the tumor.

data have shown minimal efficacy (Reddy and Williamson

the shape of the dose-response survival curve for most

Models of Cell Survival

In its simplest form, differences in tissue or tumor responses

In the changing landscape provided by IGRT technology,

Table 2.1 Advantages and disadvantages of SRS/SBRT from a

Table 2.2 BED calculation

fractionation scheme, the LQ formula will provide appropri-

Hammond EM, Dorie MJ, Giaccia AJ. ATR/ATM targets are phos-

A. Pérez-Andújar, PhD ()

© Springer International Publishing Switzerland 2016 23

Margin reduction, but consider that a large source of

Table 3.1 General comparison of conventional radiotherapy

PTV margin ≈cm ≈mm

Table 3.2 Reported accuracy of commercially available SBRT

Spine MI body fix ≈1

kV cone beam CT.

Beam energy: 6 MV photons offer the best compro-

Dose Calculation Algorithms

Treatment Platforms and Cross-Platform

Quality Assurance and Patient Safety

Linac-based Gantry-based linac Multiphoton 600 MU/min up to MLC with standard

unflattened) and leaves

Table 3.3 (continued)

Models of Cell Survival